Alternative titles; symbols
HGNC Approved Gene Symbol: APP
SNOMEDCT: 56453003;
Cytogenetic location: 21q21.3 Genomic coordinates (GRCh38) : 21:25,880,550-26,171,128 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 21q21.3 | Alzheimer disease 1, familial | 104300 | Autosomal dominant | 3 |
| Cerebral amyloid angiopathy, Dutch, Italian, Iowa, Flemish, Arctic variants | 605714 | Autosomal dominant | 3 |
Glenner and Wong (1984) purified a protein derived from the twisted beta-pleated sheet fibrils present in cerebrovascular amyloidoses and in the amyloid plaques associated with Alzheimer disease (AD; 104300). The 4.2-kD polypeptide was called the 'beta-amyloid protein' because of its partial beta-pleated sheet structure. The proteins from both disorders have an identical 28-amino acid sequence.
Masters et al. (1985) purified and characterized the cerebral amyloid protein that forms the amyloid plaque core in Alzheimer disease and in older persons with Down syndrome (190685). The protein consists of multimeric aggregates of a 40-residue polypeptide with a molecular mass of approximately 4 kD. The amino acid composition, molecular mass, and NH2-terminal sequence of this amyloid protein were found to be almost identical to those described for the amyloid deposited in the congophilic angiopathy of Alzheimer disease and Down syndrome.
Robakis et al. (1987) isolated clones corresponding to the APP gene from a human brain cDNA library. The deduced 412-residue protein contains the 28-amino acid sequence of the beta-protein located near the C terminus, suggesting that the beta-protein is cleaved posttranslationally from a larger precursor. RNA blot analysis detected a 3.3-kb mRNA transcript in brains from a normal individual, an AD patient, and a patient with Down syndrome. Tanzi et al. (1987) isolated a cDNA corresponding to the beta-amyloid protein and concluded that it is derived from a larger protein expressed in a variety of tissues.
Kang et al. (1987) isolated and sequenced an apparently full-length cDNA clone coding for the APP A4 polypeptide, a designation they used for the major protein subunit of the amyloid fibril of tangles, plaques, and blood vessel deposits in AD and Down syndrome. The predicted 695-residue precursor contains features characteristic of glycosylated integral membrane cell surface receptor proteins. Beta-amyloid, the principal component of extracellular deposits in senile plaques, is a cleavage product of the larger precursor and encompasses 28 amino acids of the ectodomain and 11 to 14 amino acids of the transmembrane domain. Kang et al. (1987) noted that this protein shows similarities to the prion protein (PRNP; 176640) found in the amyloid of transmissible spongiform encephalopathies (Oesch et al., 1985). Membrane-spanning domains of both proteins may share an amyloid-forming or amyloid-inducing potential.
Goldgaber et al. (1987) found that a 3.5-kb APP mRNA was detectable in mammalian brains and human thymus. The gene was found to be highly conserved in evolution.
Ponte et al. (1988), Tanzi et al. (1988), and Kitaguchi et al. (1988) showed that the amyloid protein precursor contains a domain very similar to the Kunitz family of serine protease inhibitors. All 3 groups found the variable presence of a 56-residue domain interpolated at residue 289 within the proposed extracellular portion of the amyloid precursor protein. The newly found amyloid protein sequence was 50% identical to bovine pancreatic trypsin inhibitor, also called aprotinin, and to the second inhibitory domain of a human plasma protein, inter-alpha-trypsin inhibitor.
Van Nostrand et al. (1989) presented evidence that protease nexin-II (PN2), a protease inhibitor that is synthesized and secreted by various cultured extravascular cells, is identical to APP.
Alternative splicing of transcripts from the single APP gene results in several isoforms of the gene product, of which APP695 is preferentially expressed in neuronal tissues (Sandbrink et al., 1994).
Yoshikai et al. (1990) determined that the APP gene contains 19 exons and spans more than 170 kb. APP has several isoforms generated by alternative splicing of exons 1-13, 13a, and 14-18. The predominant transcripts are APP695 (exons 1-6, 9-18, not 13a), APP751 (exons 1-7, 9-18, not 13a), and APP770 (exons 1-18, not 13a). All of these encode multidomain proteins with a single membrane-spanning region. They differ in that APP751 and APP770 contain exon 7, which encodes a serine protease inhibitor domain. APP695 is a predominant form in neuronal tissues, whereas APP751 is the predominant variant elsewhere. The beta-amyloid protein is encoded by exons 16 and 17.
By somatic cell hybridization, Kang et al. (1987) and Goldgaber et al. (1987) mapped the A4 peptide gene to chromosome 21.
By in situ hybridization, Robakis et al. (1987), localized the APP gene to the proximal part of chromosome 21q21. Tanzi et al. (1987) mapped the APP gene to 21q11.2-q21 by analysis of somatic cell hybrid cDNAs. Zabel et al. (1987) mapped the APP gene to 21q21 by in situ hybridization. They placed it near or in the 21q21-q22.1 segment, a somewhat more distal location than that suggested by Robakis et al. (1987). Blanquet et al. (1987) assigned the APP locus to 21q21.3-q22.11. Using in situ hybridization and Southern blot techniques on skin fibroblast lines carrying translocations involving chromosome 21, Jenkins et al. (1988) found that the APP gene is located within the region 21q11.2-q21.05.
By studies of a somatic cell hybrid mapping panel, in situ hybridization, and transverse-alternating-field electrophoresis, Patterson et al. (1988) showed that the APP gene is located very near the 21q21/21q22 border and probably within the region of chromosome 21 that, when trisomic, results in Down syndrome. However, Korenberg et al. (1989) concluded that the APP gene is located outside the minimal region producing the classic phenotypic features of Down syndrome.
By studies of DNA from a panel of somatic cell hybrids, Lovett et al. (1987) mapped the mouse App gene to chromosome 16. Cheng et al. (1987) also mapped the mouse App gene to chromosome 16 using genetic linkage studies.
Posttranslational Processing
APP undergoes posttranslational proteolytic processing by alpha-, beta-, and gamma-secretases. Alpha-secretase generates soluble amyloid protein, while beta- and gamma-secretases generate APP components with amyloidogenic features. These 2 processing pathways are mutually exclusive (Sennvik et al., 2000).
Esch et al. (1990) demonstrated that APP undergoes constitutive processing to yield a secretory product. This constitutive cleavage by an alpha-secretase occurs in the interior of the amyloid peptide sequence, thereby precluding formation and deposition of the beta-amyloid protein. Tagawa et al. (1991) demonstrated that this APP secretase is identical to cathepsin B (CTSB; 116810).
Beta-amyloid production is initiated by the beta-secretase cleavage of APP in the extracellular domain, which results in the production of the APP C-terminal fragment C99. Vassar et al. (1999) and Yan et al. (1999) identified and characterized the APP beta-secretase (BACE1; 604252), which is membrane-bound. This fragment is further cleaved by gamma-secretase at residues 40-42 to generate beta-amyloid-40 and beta-amyloid-42. The gamma-secretase cleavage site is centered within the transmembrane domain (Grimm et al., 2005). Cleavage also occurs at APP residues 48-50, termed the epsilon site, which generates a 59-residue cytosolic stub referred to as beta-APP intracellular domain (AICD). The gamma-secretase and epsilon-site proteolytic activities are often collectively termed gamma-secretase (Pardossi-Piquard et al., 2005).
De Strooper et al. (1998) demonstrated that presenilin-1 (PSEN1; 104311) is involved in gamma-secretase-mediated proteolytic cleavage of the C-terminal transmembrane fragments of APP after their generation by beta-secretase. In vitro studies of cultured neuronal cells derived from PSEN1-deficient mice showed a selective decrease in the production of the amyloidogenic peptide beta-amyloid-42 by proteolytic processing of APP.
Gervais et al. (1999) found that APP is directly cleaved within the cytoplasmic tail by caspases, predominantly caspase-3 (CASP3; 600636). Cleavage occurred in apoptotic hippocampal neurons in vivo following acute excitotoxic or ischemic brain injury, and resulted in beta-peptide formation. Accordingly, increased levels of caspase-3 were identified in dying neurons of Alzheimer disease brains. Gervais et al. (1999) concluded that caspases play a dual role in proteolytic processing of APP and the resulting propensity for amyloid beta peptide formation, as well as in the ultimate apoptotic death of neurons in Alzheimer disease.
Kojro et al. (2001) found that ADAM10 (602192) has alpha-secretase activity that mediates the effect of cholesterol on APP metabolism. Treatment of various peripheral and neural human cell lines with either a cholesterol-extracting agent or an HMG-CoA reductase (HMGCR; 142910) inhibitor resulted in a drastic increase of secreted alpha-secretase-cleaved soluble APP peptides. The stimulatory effect was further increased in cells overexpressing ADAM10. In cells overexpressing APP, the increase in alpha-secretase activity resulted in decreased secretion of amyloidogenic beta-secretase-generated APP peptides. Western blot analysis confirmed that HMGCR inhibition increased expression of ADAM10. Kojro et al. (2001) concluded that cholesterol reduction promotes the nonamyloidogenic alpha-secretase pathway and formation of neuroprotective soluble alpha-secretase APP peptides.
Wilson et al. (2002) analyzed the production of several forms of secreted and intracellular amyloid beta in mouse cells lacking PSEN1, PSEN2 (600759), or both proteins. Although most amyloid beta species were abolished in PSEN1/PSEN2 -/- cells, the production of intracellular A-beta-42 generated in the endoplasmic reticulum/intermediate compartment was unaffected by the absence of these proteins, either singly or in combination. Wilson et al. (2002) concluded that production of this pool of amyloid beta occurs independently of PSEN1/PSEN2, and, therefore, another gamma-secretase activity must be responsible for cleavage of APP within the early secretory compartments.
Francis et al. (2002) observed a reduction in gamma-secretase cleavage of beta-APP after RNA-mediated interference assays to inactivate Aph1 (see APH1A; 607629), Pen2 (607632), or nicastrin (NCSTN; 605254) in cultured Drosophila cells. They concluded that APH1 and PEN2 are required for gamma-secretase cleavage of beta-APP, as well as for Notch pathway signaling and presenilin protein accumulation.
Gamma-secretase activity requires the formation of a stable, high molecular mass protein complex that, in addition to the endoproteolyzed fragmented form of presenilin, contains essential cofactors including NCSTN, APH1, and PEN2. Takasugi et al. (2003) showed that Drosophila APH1 increased the stability of Drosophila presenilin holoprotein in the complex. Depletion of PEN2 by RNA interference prevented endoproteolysis of presenilin and promoted stabilization of the holoprotein in both Drosophila and mammalian cells, including primary neurons. Coexpression of Drosophila PEN2 with APH1 and NCSTN increased the formation of presenilin fragments as well as gamma-secretase activity. Takasugi et al. (2003) concluded that APH1 stabilizes the presenilin holoprotein in the complex, whereas PEN2 is required for endoproteolytic processing of presenilin and conferring gamma-secretase activity to the complex.
In transgenic mice overexpressing human beta-secretase BACE1 (604252), Lee et al. (2005) found that modest BACE1 overexpression enhanced amyloid deposition, but high BACE1 overexpression inhibited amyloid formation despite increased beta-cleavage of App. High BACE1 expression shifted the subcellular location of App cleavage from axons and axon terminals to the neuronal perikarya and diminished the anterograde axonal transport of mature phosphorylated isoforms of App. Lee et al. (2005) concluded that amyloid beta generated proximally in neuronal perikarya has a different fate than amyloid beta generated at or near the synapse.
In mouse neuroblastoma cells, Cai et al. (2006) found that overexpression of catalytically active phospholipase D1 (PLD1; 602382) promoted generation of beta-amyloid-containing vesicles from the trans-Golgi network. Although PLD1 enzymatic activity was decreased in neurons with familial Alzheimer disease-3 (AD3; 607822) PSEN1 mutations, overexpression of wildtype PLD1, but not catalytically inactive PLD1, in these cells increased cell surface delivery of beta-amyloid at axonal terminals and rescued impaired axonal growth and neurite branching. The findings showed that catalytically active PLD1 regulates intracellular trafficking of beta-amyloid.
Pastorino et al. (2006) demonstrated that PIN1 (601052) has profound effects on APP processing and amyloid beta production. They found that PIN1 binds to the phosphorylated thr668-to-pro motif in APP and accelerates its isomerization by over 1,000-fold, regulating the APP intracellular domain between 2 conformations, as visualized by NMR. Whereas Pin1 overexpression reduces amyloid beta secretion from cell cultures, knockout of Pin1 increases its secretion. Pin1 knockout alone or in combination with overexpression of mutant APP in mice increases amyloidogenic APP processing and selectively elevates insoluble amyloid beta-42, a major toxic species, in brains in an age-dependent manner, with amyloid beta-42 being prominently localized to multivesicular bodies of neurons, as shown in Alzheimer disease before plaque pathology. Thus, Pastorino et al. (2006) concluded that PIN1-catalyzed prolyl isomerization is a novel mechanism to regulate APP processing and amyloid beta production, and its deregulation may link both tangle and plaque pathologies.
In HEK293 cells in vitro, Ni et al. (2006) found that activation of beta-2-adrenergic receptors (ADRB2; 109690) stimulated gamma-secretase activity and beta-amyloid production. The stimulation involved the association of ADRB2 with PSEN1 and required agonist-induced endocytosis of ADRB2. Similar effects were observed after activation of the opioid receptor OPRD1 (165195). In mouse models of AD, chronic treatment with ADRB2 agonists increased cerebral amyloid plaques, and treatment with ADRB2 antagonists reduced cerebral amyloid plaques. Ni et al. (2006) postulated that abnormal activation of ADRB2 receptors may contribute to beta-amyloid accumulation in AD.
Munter et al. (2007) showed that an amino-acid motif GxxxG in the transmembrane sequence (TMS) of APP has a regulatory impact on the type of beta-amyloid species produced by gamma-secretase. In general, GxxxG motifs form the basis for helix-helix interaction in the dimerization of transmembrane proteins. The APP TMS contains 3 consecutive GxxxG motifs encompassing residues 621 to 633 of APP695 or beta-amyloid residues 25 to 37. In vitro studies of neuronal cells showed that mutations within the G29xxxG33 region reduced dimerization strength in the transmembrane region, affecting gamma-secretase cleavage sites, and resulting in decreased levels of beta-42 and increased levels of shorter beta-amyloid species, such as beta-37, beta-35, and beta-34. Munter et al. (2007) suggested that events that stabilize the dimerization of APP may facilitate generation of beta-amyloid-42. By transfection of human neuroblastoma cells, Munter et al. (2010) found that increased A-beta-42 generation by APP-FAD mutations could be rescued in vitro by GxxxG mutations. The combination of the APP G33A mutation with APP-FAD mutations yielded a 60% decrease of A-beta-42 levels and a concomitant 3-fold increase of A-beta-38 levels compared to wildtype. However, the effects of the G33A mutation were attenuated in the presence of PSEN1-FAD mutations, indicating a different mechanism of PSEN1-FAD mutants compared to APP-FAD mutants. The results further illustrated how APP is processed by gamma-secretase, and emphasized the potential of the GxxxG motif in the prevention of AD.
Faghihi et al. (2008) identified a conserved noncoding antisense BACE1 transcript (BACE1-AS) that concordantly regulated BACE1 mRNA and protein levels in a dose-dependent manner. Various cell stressors, including beta-amyloid-42, resulted in increased levels of BACE1-AS, increased BACE1 mRNA stability, and the generation of additional beta-amyloid through a posttranscriptional feed-forward mechanism. BACE1-AS transcript concentrations in postmortem brain tissue from AD patients were elevated up to 6-fold, with an average increase of about 2-fold across all brain regions. Similar changes were observed in transgenic AD mice. In a human cell line with an AD-inducing APP mutation, knockdown of BACE1-AS resulted in decreased concentrations of both beta-amyloid-40 and -42. Faghihi et al. (2008) suggested that neurons use BACE1-AS to maintain precise regulation of BACE1 expression and that alterations in this regulation resulting in increased BACE1 activity may contribute to the pathogenesis of AD via changes in beta-amyloid processing.
Schobel et al. (2008) found that SNX33 (619107) activated alpha-secretase cleavage of APP to increase APP alpha shedding. The SH3 domain of SNX33 was required, but was not sufficient, for the effect on APP shedding. SNX33 expression slowed the rate of APP endocytosis and transferrin (TF; 190000) uptake by binding to and inhibiting dynamin (see 602377), which led to increased APP at the plasma membrane followed by enhanced cleavage by alpha-secretase.
Chu and Pratico (2011) showed that 5-lipoxygenase (5-LO) (ALOX5; 152390) regulated the formation of beta-amyloid by directly activating CREB (123810), which in turn increased transcription of the proteins involved in the gamma-secretase complex. Studies were performed in human neuroblastoma cells transfected with an Alzheimer disease-associated mutation in the APP gene (104760.0008). Pharmacologic inhibition or ALOX5 gene disruption resulted in a significant decrease of beta-amyloid production and gamma-secretase levels. Transgenic mice with the APP mutation had increased levels of 5-LO compared to controls, and treatment with a 5-LO inhibitor decreased beta-amyloid levels in the brain. Alox5-null mice had lower levels of beta-amyloid-40 and -42 species. Chu and Pratico (2011) suggested a novel functional role for 5-LO in regulating endogenous amyloid formation in the central nervous system.
Ranganathan et al. (2011) found that expression of endogenous Ldlrad3 (617986) partly overlapped with that of App in mouse hippocampal HT22 cells. App coimmunoprecipitated from mouse brain extracts with Lldrad3, and LDLRAD3 also coimmunoprecipitated specifically with APP from transfected COS-1 cells. Solid-phase binding assays demonstrated that LDLRAD3 specifically interacted with the C terminus of APP. Interaction of LDLRAD3 with APP was not affected by Fe65 (APBB1; 602709), which interacts with both APP and polyproline regions like that found in LDLRAD3, and LDLRAD3 did not coimmunoprecipitate with Fe65. Transfection of COS-1 or CHO-13-5-1 cells with LDLRAD3 led to a decrease in secreted APP, an increase in production of A-beta peptide, and an increase in APP turnover, but it did not affect levels of cellular APP, suggesting that LDLRAD3 functions in APP processing.
Zhao et al. (2012) found that full-length isoform 1 of CUTA (616953) interacted with BACE1 mainly in the Golgi/TGN. Overexpression of CUTA isoform 1 reduced BACE1-mediated APP processing in the Golgi/TGN and reduced A-beta secretion. Knockdown of CUTA isoform 1 reduced cell surface BACE1 and increased APP processing and A-beta secretion. Zhao et al. (2012) concluded that CUTA isoform 1 is a BACE1-interacting protein that mediates intracellular trafficking of BACE1 and inhibits BACE1-dependent processing of APP to A-beta.
Hou et al. (2015) found that overexpression of full-length human CUTA isoform 1 increased copper content in mouse neuroblastoma N2a cells in a dose-dependent manner. Copper increased Cuta mRNA and protein in a dose-dependent manner, suggesting positive feedback. In AD model mouse cells, copper and CUTA isoform 1 up- and downregulated APP processing, respectively. Whereas copper increased App expression and processing, CUTA isoform 1 reduced App processing via Bace1, but it had no effect on App expression. Both copper and Cuta were downregulated in hippocampus of AD model mice compared with controls.
Willem et al. (2015) described a physiologic APP processing pathway that generates proteolytic fragments capable of inhibiting neuronal activity within the hippocampus. The authors identified higher molecular mass carboxy-terminal fragments (CTFs) of APP, termed CTF-eta, in addition to the long-known CTF-alpha and CTF-beta fragments generated by the alpha- and beta-secretases ADAM10 (602192) and BACE1 (604252), respectively. CTF-eta generation is mediated in part by membrane-bound matrix metalloproteinases such as MT5-MMP (604871), referred to as eta-secretase activity. Eta-secretase cleavage occurs primarily at amino acids 504-505 of APP(695), releasing a truncated ectodomain. After shedding of this ectodomain, CTF-eta is further processed by ADAM10 and BACE1 to release long and short A-eta peptides (termed A-eta-alpha and A-eta-beta). CTFs produced by eta-secretase are enriched in dystrophic neurites in an AD mouse model and in human AD brains. Genetic and pharmacologic inhibition of BACE1 activity results in robust accumulation of CTF-eta and A-eta-alpha. In mice treated with a potent BACE1 inhibitor, hippocampal long-term potentiation was reduced. Notably, when recombinant or synthetic A-eta-alpha was applied on hippocampal slices ex vivo, long-term potentiation was lowered. Furthermore, in vivo single-cell 2-photon calcium imaging showed that hippocampal neuronal activity was attenuated by A-eta-alpha.
Paschkowsky et al. (2016) found that human RHBDL4 (617515) interacted with and cleaved APP in the ER, leading to the generation of multiple APP N- and C-terminal fragments intracellularly. These APP fragments were neither generated nor degraded by classical secretases, and likely not by other proteases. RHBDL4 activity resulted in a significant decrease of secreted amyloid-beta protein levels. The results identified processing of APP by RHBDL4 as an alternative APP-processing pathway bypassing the classical amyloidogenic pathway. In addition, the authors found that RHBDL4 also cleaved other APP family members, including APLP1 and APLP2.
Paschkowsky et al. (2018) found that cellular cholesterol levels regulated RHBDL4-mediated APP processing, with increasing levels of cholesterol negatively impacting RHBDL4 activity and decreasing cholesterol levels triggering RHBDL4 activity. Although APP itself binds cholesterol, direct binding of cholesterol to APP did not regulate substrate recognition. Instead, the authors identified cholesterol-binding motifs in RHBDL4, and further analysis showed that RHBDL4 bound cholesterol and that this interaction regulated RHBDL4 activity.
Cellular Growth and Apoptosis
Adler et al. (1991) demonstrated a dramatic increase in APP mRNA production and a more modest increase in the APP protein synthesized in senescent cultured fibroblasts compared with early-passage proliferating fibroblasts. In addition, induction of quiescence by serum deprivation reversibly induced an increase in amyloid mRNA and protein levels. The investigators hypothesized that the amyloid precursor protein may play an important role in the cellular growth and metabolic responses to serum and growth factors under both physiologic and pathologic conditions.
Kamenetz et al. (2003) found that neuronal activity modulated the formation and secretion of beta-amyloid peptides in rat hippocampal slice neurons that overexpressed APP. Beta-amyloid in turn selectively depressed excitatory synaptic transmission onto neighboring neurons. Kamenetz et al. (2003) proposed that activity-dependent modulation of endogenous beta-amyloid may normally participate in a negative feedback that could keep neuronal hyperactivity in check.
Du et al. (2018) found that the expression of PKC-delta (176977) and BACE1 is elevated in AD. PKC-delta downregulation in a human neuroblastoma cell line and a PKC-delta knockout mouse cell line reduced BACE1 expression, BACE1-mediated APP processing, and beta-amyloid protein production. PKC-delta overexpression in a mouse neuroblastoma cell line upregulated BACE1 expression and beta-amyloid protein production. Modulation of the expression levels of PKC-delta in human and mouse cells further revealed that downregulation of PKC-delta decreased IKB-alpha (NFKBIA; 164008) and p65 (RELA; 164014) phosphorylation, whereas overexpression increased phosphorylation. PKC-delta-dependent phosphorylation of IKB-alpha and p65 upregulated BACE1 expression to enhance beta-amyloid protein production. Treatment of double-transgenic APP/PS1 (104311) mice, which model AD, with the PKC-delta inhibitor rottlerin significantly improved spatial learning and memory, rescued cognitive deficits, and reduced beta-amyloid protein production and deposition in brain. Further, in cell lines and double-transgenic mice, reduction of PKC-delta expression reduced BACE1 expression through mediating IKB-alpha/p65 phosphorylation, thereby attenuating BACE1-mediated APP processing and beta-amyloid protein production.
Secreted APP (sAPP) Protease Inhibitor Activity
Smith et al. (1990) showed that the platelet inhibitor of coagulation factor XI (264900) is a secreted form of APP. Schmaier et al. (1993) provided biochemical evidence that APP, also known as PN2, may serve as a cerebral anticoagulant. Schmaier et al. (1993) found that APP is also a potent inhibitor of factor IXa (300746) and that it forms a complex with factor IXa as detected by gel filtration and ELISA. They suggested that this fact may explain the spontaneous intracerebral hemorrhages seen in patients with hereditary cerebral hemorrhage with amyloidosis of the Dutch type (605714) in which there is extensive accumulation of beta-amyloid in cerebral blood vessels.
Brody et al. (2008) used intracerebral microdialysis to obtain serial brain interstitial fluid (ISF) samples in 18 patients who were undergoing invasive intracranial monitoring after acute brain injury. They found a strong positive correlation between changes in brain ISF amyloid beta concentrations and neurologic status, with amyloid beta concentrations increasing as neurologic status improved and falling when neurologic status declined. Brain ISF amyloid beta concentrations were also lower when other cerebral physiologic and metabolic abnormalities reflected depressed neuronal function. Brody et al. (2008) concluded that such dynamics fit well with the hypothesis that neuronal activity regulates extracellular amyloid beta concentrations.
Interaction with Intracellular Adaptor Proteins and Effect on Gene Transcription
Gamma-secretase cleavage of APP produces the extracellular amyloid beta peptide of AD and releases an intracellular tail fragment (AICD). Cao and Sudhof (2001) demonstrated that the cytoplasmic tail of APP forms a multimeric complex with the nuclear adaptor protein Fe65 (APBB1; 602709) and the histone acetyltransferase TIP60 (601409). This complex potently stimulates transcription via heterologous Gal4 or LexA DNA binding domains, suggesting that release of the cytoplasmic tail of APP by gamma-cleavage may function in gene expression.
Baek et al. (2002) demonstrated that interleukin-1-beta (IL1B; 147720) caused nuclear export of a specific NCOR (600849) corepressor complex, resulting in derepression of a specific subset of nuclear factor-kappa-B (NFKB; see 164011)-regulated genes. Nuclear export of the NCOR/TAB2 (605101)/HDAC3 (605166) complex by IL1B was temporally linked to selective recruitment of a TIP60 coactivator complex. KAI1 was also directly activated by a ternary complex, dependent on the acetyltransferase activity of TIP60, that consists of the presenilin-dependent C-terminal cleavage product of APP, FE65, and TIP60. The findings identified a specific in vivo gene target of an APP-dependent transcription complex in the brain.
Taru et al. (2002) reported that the GYENPTY motif within the cytoplasmic domain of APP interacts with the C-terminal phosphotyrosine interaction domain of JIP1 (MAPK8IP1; 604641). They found that a specific splice variant of JIP1, designated JIP1B, modulated the processing of APP in an interaction-dependent manner following coexpression in mouse neuroblastoma cells. JIP1B expression stabilized immature APP and suppressed secretion of the large extracellular N-terminal domain of APP, release of the intracellular C-terminal fragment, and secretion of beta-amyloid-40 and -42. These effects required the phosphotyrosine interaction domain of JIP1B, but not the JNK-binding domain, indicating that the modulation of APP metabolism was independent of the JNK signaling cascade.
Proteolytic processing that generates beta-amyloid also releases into the cytoplasm a C-terminal fragment of APP termed C-gamma. Using a mouse catecholaminergic (CAD) cell line and an antibody to APP695 phosphorylated at thr668 (pAPP), Muresan and Muresan (2004) showed that C-gamma was localized to intranuclear speckles with RNU2B and serine/arginine-rich proteins (see SFRS1; 600812) but was excluded from the coiled bodies and the gems. Subnuclear localization occurred independent of differentiation state in CAD cells and was also present in other mammalian neural, epithelial, and fibroblast cells. Exogenously expressed C-gamma became phosphorylated and distributed throughout the cell, and a fraction of this C-gamma was translocated into the nucleus, where it colocalized with endogenous pAPP epitopes. Fe65 (APBB1; 602709) colocalized with pAPP epitopes and with expressed C-gamma at intranuclear speckles. Muresan and Muresan (2004) suggested that phosphorylated C-gamma may accumulate at the splicing factor compartment and that APP may play a role in pre-mRNA splicing that is regulated by Fe65 and APP phosphorylation.
In animal cell culture studies, Pardossi-Piquard et al. (2005) found that endogenous gamma-secretase-dependent AICD fragments from APP-like proteins, including APP, APLP1 (104775) and APLP2 (104776), induced transcriptional activation of neprilysin (MME; 120520) by binding to its promoter. Neprilysin, in turn, was partly responsible for the degradation of beta-amyloid-40. Psen1/Psen2-deficient mouse fibroblasts or blastocysts were unable to efficiently degrade beta-amyloid-40 due to decreased neprilysin activity and protein expression. Single Psen1-deficient or Psen2-deficient cells had normal levels of neprilysin protein and activity, indicating that depletion of both Psen genes was necessary to affect transcription of neprilysin. The findings provided evidence for a regulatory mechanism in which varying levels of gamma-secretase activity modulate beta-amyloid degradation via AICD fragments. Chen and Selkoe (2007) questioned the findings of Pardossi-Piquard et al. (2005) and provided their own experimental evidence that neprilysin levels and/or activity were not affected by lack of APP, Psen1/Psen2 genotypes, or inhibition of gamma-secretase. In response, Pardossi-Piquard et al. (2007) defended their original findings and provided further evidence that Psen complexes and AICD modulate neprilysin expression in some cells.
Mitochondria
Kaneko et al. (1995) demonstrated that nanomolar concentrations of various synthetic beta-amyloids specifically impaired mitochondrial succinate dehydrogenase (SDH; see, e.g., 185470), and speculated that one of the primary targets of beta-amyloids is the mitochondrial electron transport chain.
Lipid Homeostasis
Simons et al. (1998) found that pharmacologic reduction of cellular cholesterol in cultured rat hippocampal neurons resulted in a striking inhibition of beta-amyloid synthesis, while secreted APP was unperturbed. The effects appeared to be mediated by inhibition of beta-secretase cleavage. In mouse embryonic fibroblasts, Grimm et al. (2005) found that beta-amyloid-42 directly activated neutral sphingomyelinase (SMPD2; 603498) and downregulated sphingomyelinase levels, whereas beta-amyloid-40 reduced de novo cholesterol synthesis by inhibition of HMG-CoA reductase (HMGCR; 142910). These processes were dependent on gamma-secretase activity, suggesting that a proteolytic APP fragment is involved in lipid homeostasis.
Using knockout mice, reporter gene assays, and chromatin immunoprecipitation analysis, Liu et al. (2007) found that AICD, together with Fe65 (APBB1; 602709) and Tip60 (KAT5; 601409), modulated brain Apoe and cholesterol metabolism by suppressing expression of low density lipoprotein receptor-related protein-1 (LRP1; 107770).
APP Transport
Tang et al. (1996) presented evidence suggesting that postmenopausal estrogen replacement therapy may prevent or delay the onset of AD. Xu et al. (1998) demonstrated that physiologic levels of 17-beta-estradiol reduced the generation of beta-amyloid by neuroblastoma cells and by primary cultures of rat, mouse, and human embryonic cerebrocortical neurons. These results suggested a mechanism by which estrogen replacement therapy could delay or prevent AD. By analyzing the effect of 17-beta-estradiol on mouse and rat primary neuronal cultures and a neuroblastoma cell line, Greenfield et al. (2002) determined that the beneficial effect of estrogen is mediated by accelerated trafficking of beta APP through the trans-Golgi network (TGN), which precludes maximal beta-amyloid production. Seventeen-beta-estradiol stimulated formation of vesicles containing APP, modulated TGN phospholipid levels, particularly those of phosphatidylinositol, and recruited soluble trafficking factors to the TGN. Greenfield et al. (2002) concluded that altering the kinetics of APP transport can influence its metabolic fate.
Kang et al. (2000) noted that alpha-2-macroglobulin (A2M; 103950), had been shown to mediate the clearance and degradation of beta-amyloid via its receptor, the low density lipoprotein receptor-related protein-1 (LRP1; 107770) (Kounnas et al., 1995; Narita et al., 1997). Kang et al. (2000) showed in vitro that LRP1 is required for the A2M-mediated clearance of beta-amyloid-40 and -42 via receptor-mediated cellular uptake. Analysis of postmortem human brain tissue showed that LRP expression normally declines with age, and that LRP expression in AD brains was significantly lower than in controls. Within the AD group, higher LRP levels were correlated with later age of onset of AD and death. Kang et al. (2000) concluded that reduced LRP expression is a contributing risk factor for AD, possibly by impeding the clearance of soluble beta-amyloid.
Kamal et al. (2000) demonstrated that the axonal transport of APP in neurons is mediated by the direct binding of APP to the kinesin light chain (KNS2; 600025) subunit of kinesin I. Kamal et al. (2001) identified an axonal membrane compartment containing APP, beta-secretase, and presenilin-1. The fast anterograde axonal transport of this compartment was mediated by APP and kinesin I. They found that proteolytic processing of APP occurred in the compartment in vitro and in vivo in axons, generating amyloid beta and a carboxy-terminal fragment of APP and liberating kinesin-I from the membrane. Kamal et al. (2001) concluded that APP functions as a kinesin-I membrane receptor, mediating the axonal transport of beta-secretase and presenilin-1, and that processing of APP to amyloid beta by secretases can occur in an axonal membrane compartment transported by kinesin-I.
The 5-prime untranslated region of APP mRNA contains a functional iron-responsive element stem loop such that APP translation is increased in response to cytoplasmic free iron levels. Duce et al. (2010) found that neuronal APP possesses ferroxidase activity mainly via the REXXE motif in the E2 domain and that this activity could be inhibited by zinc. Suppression of APP using siRNA in HEK293T cells resulted in an accumulation of iron. Moreover, primary cortical neurons from App-null mice also accumulated iron due to a decrease in iron efflux, and App-null mice were more vulnerable to dietary iron exposure compared to controls. APP in human and mouse cortical tissue interacted with ferroportin (SLC40A1; 604653) to facilitate iron transport. Postmortem cortical tissue from patients with Alzheimer disease showed an increase in iron compared to controls, and the increase was shown to be due to inhibition of APP ferroxidase activity by endogenous zinc, which originated from zinc-laden amyloid aggregates and correlated with beta-amyloid burden. The study identified APP as a functional ferroxidase similar to ceruloplasmin (CP; 117700) in cortical neurons, which apparently plays a role in preventing iron-mediated oxidative stress. The findings suggested that abnormal exchange of cortical zinc may link amyloid pathology to neuronal iron accumulation in Alzheimer disease.
Using Western blot analysis, Stieren et al. (2011) found that UBQLN1 (605046) expression was reduced in postmortem AD brain at all stages of AD development except the earliest preclinical stage. UBQLN1 downregulation preceded significant neuronal cell loss in preclinical samples. Yeast 2-hybrid analysis of a rat brain cDNA library showed that human UBQLN1 interacted with the APP intracellular domain. UBQLN1 also immunoprecipitated with APP in cotransfected HeLa cells. The amount of UBQLN1 that coprecipitated with APP increased following crosslinking, suggesting that the complex was transient. Coexpression of UBQLN1 with APP reduced the content of amyloid deposits in APP-overexpressing rat PC12 cells and reduced production of pathogenic amyloid-beta peptides produced by APP-expressing HeLa cells. In vitro, UBQLN1 significantly protected a test protein against heat denaturation. Stieren et al. (2011) concluded that UBQLN1 functions as a chaperone for APP and that diminished UBQLN1 levels in AD may contribute to pathogenesis.
Somatic Gene Recombination
Lee et al. (2018) described recombination of the APP gene in normal and Alzheimer disease neurons occurring mosaically as thousands of variant 'genomic cDNAs' (gencDNAs). GencDNAs lacked introns and ranged from full-length cDNA copies of expressed, brain-specific RNA splice variants to myriad smaller forms that contained intra-exonic junctions, insertions, deletions, and/or single-nucleotide variations. DNA in situ hybridization identified gencDNAs within single neurons that were distinct from wildtype loci and absent from nonneuronal cells. Mechanistic studies supported neuronal 'retro-insertion' of RNA to produce gencDNAs; this process involved transcription, DNA breaks, reverse transcriptase activity, and age. Lee et al. (2018) suggested that neuronal gene recombination may allow 'recording' of neural activity for selective 'playback' of preferred gene variants whose expression bypasses splicing, and that this has implications for cellular diversity, learning and memory, plasticity, and diseases of the human brain.
Modulation of Synaptic Transmission
Rice et al. (2019) found that the secreted APP extension domain directly bound the sushi-1 domain specific to GABBR1 (603540). Secreted APP-GABBR1 binding suppressed synaptic transmission and enhanced short-term facilitation in mouse hippocampal synapses via inhibition of synaptic vesicle release. A 17-amino acid peptide corresponding to the GABBR1 binding region within APP suppressed in vivo spontaneous neuronal activity in the hippocampus of anesthetized transgenic mice expressing the genetically encoded calcium indicator GCaMP6s under the Thy1 promoter (Thy1-GCaMP6s mice). Rice et al. (2019) concluded that secreted APP acts as a GABBR1-specific ligand to suppress synaptic vesicle release, consequently modulating hippocampal synaptic plasticity and neurotransmission in vivo.
Yan et al. (1996) reported that the AGER protein (600214), called RAGE (receptor for advanced glycation end products) by them, is an important receptor for the amyloid beta peptide and that expression of this receptor was increased in Alzheimer disease. They noted that expression of RAGE was particularly increased in neurons close to deposits of amyloid beta peptide and to neurofibrillary tangles.
Multhaup et al. (1996) demonstrated that the amyloid precursor protein is involved in copper reduction. They postulated that copper-mediated toxicity may contribute to neurodegeneration in Alzheimer disease, possibly by increased production of hydroxyl radicals. Simons et al. (2002) discussed studies indicating that the binding of copper to the copper-binding domain (CuBD) of APP, which is located in the N-terminal cysteine-rich region, reduced amyloid beta production to undetectable levels and stimulated the nonamyloidogenic pathway of APP metabolism. They compared the properties of the CuBD of mammalian APP with the CuBDs of homologous proteins from X. laevis, C. elegans, and Drosophila. All APP homologs, with and without conserved histidines, bound Cu(2+). An examination of Cu(2+)-binding and -reducing activities indicated phylogenic divergence. While CuBDs from ancestral APP-like proteins bind Cu(2+) tightly, CuBDs from APP of higher species display a gain of activity in Cu(2+) reduction and Cu(+) release.
Di Luca et al. (1998) found that the ratio of the 130-kD isoform to that of lower molecular weight 106- to 110-kD isoforms of APP was significantly altered in platelet membranes derived from Alzheimer patients compared with that in controls. No differences were observed in the relative levels of mRNA corresponding to the 3 major transcripts, APP770, APP751, and APP695. The authors suggested that Alzheimer disease is a systemic disorder, with oversecretion of APP751 and APP770 as well as an alteration of processing of mature APP in platelets and neurons.
Van Leeuwen et al. (1998) identified aberrant forms of both APP and ubiquitin-B (UBB; 191339) in neurofibrillary tangles, neuritic plaques, and neuropil threads in the cerebral cortex of patients with AD and Down syndrome. Both aberrant proteins had deletions at the C terminus. The aberrant APP protein is a 348-residue truncated protein with a wildtype N-terminus and an aberrant C terminus translated in the +1 reading frame; it is thus designated 'APP+1.' Both UBB+1 and APP+1 displayed cellular colocalization, suggesting a common origin of the defect. Further analysis suggested the presence of a transcriptional dinucleotide deletion in both +1 proteins. Van Leeuwen et al. (1998) noted that the GAGAGAGA motif in exon 9 of the APP gene is an extended version of the GAGAG in the vasopressin gene (AVP; 192340), in which a destabilizing dinucleotide GA deletion had been identified in vasopressin-deficient rats. Van Leeuwen et al. (1998) stated that although this transcriptional dinucleotide deletion is probably not limited to postmitotic cells, postmitotic aging neurons are less capable of compensating for transcript-modifying activity and may thus be particularly sensitive to the accumulation of frameshifted proteins. Hol et al. (2003) demonstrated that the APP+1 protein is secreted from human neurons. Postmortem cortex samples from 122 AD patients had increased levels of APP+1 compared to cortex of 50 nondemented controls. Postmortem CSF of AD patients had significantly lower levels of APP+1 compared to CSF of controls. In addition, the level of CSF APP+1 was inversely correlated with the severity of the neuropathology. Hol et al. (2003) concluded that APP+1 is normally secreted by neurons, thus preventing intraneuronal accumulation of APP+1 in brains of nondemented controls without neurofibrillary pathology. Van Leeuwen et al. (2006) found that the aberrant APP+1 protein was present in neurons with beaded fibers in young individuals with Down syndrome in the absence of any pathologic hallmarks of AD. Both APP+1 and UBB+1 were present within brain neurofibrillary tangles and neuritic plaques from older DS patients and patients with various forms of autosomal dominant AD. Moreover, APP+1 and UBB+1 were detected in the neuropathologic hallmarks of other tau (MAPT; 157140)-related dementias, including Pick disease (172700), progressive supranuclear palsy (PSP; 601104), and less commonly frontotemporal dementia (FTD; 600274). Van Leeuwen et al. (2006) postulated that accumulation of APP+1 and UBB+1 contributes to various forms of dementia.
Using immunoprecipitation studies, Takahashi et al. (2000) showed that APP and amyloid precursor-like protein (APLP1; 104775) bound to HMOX1 (141250) and HMOX2 (141251) in the endoplasmic reticulum and inhibited heme oxygenase activity by 25 to 35% in vitro. FAD-associated APP mutations showed greater inhibition (45 to 50%) of heme oxygenase. As heme oxygenase shows antioxidative effects, the authors hypothesized that APP-mediated inhibition of heme oxygenase may result in increased oxidative neurotoxicity in AD.
Lorenzo et al. (2000) demonstrated that conversion of amyloid beta to the fibrillar form in vitro markedly increased binding to specific neuronal membrane proteins, including APP itself. Nanomolar concentration of fibrillar amyloid beta bound cell surface holo-APP in rat cortical neurons. App-null neurons showed reduced vulnerability to beta-amyloid neurotoxicity, suggesting that beta-amyloid neurotoxicity involves APP. The findings suggested that APP may be one of the major cell surface mediators of amyloid beta toxicity, but that some toxic effects are due to other mechanisms (Senior, 2000).
Using Western blotting, immunoprecipitation assays, and surface plasmon resonance analysis, Guo et al. (2006) showed that beta-amyloid-40 and -42 formed stable complexes with soluble tau (MAPT; 157140) and that prior phosphorylation of tau inhibited complex formation. Immunostaining of brain extracts from patients with AD and controls showed that phosphorylated tau and beta-amyloid were present within the same neuron. Guo et al. (2006) postulated that an initial step in AD pathogenesis may be the intracellular binding of soluble beta-amyloid to soluble nonphosphorylated tau.
Using in vivo microdialysis in mice, Kang et al. (2009) found that the amount of brain interstitial fluid (ISF) amyloid-beta correlated with wakefulness. The amount of ISF amyloid-beta also significantly increased during acute sleep deprivation and during orexin (602358) infusion, but decreased with infusion of a dual orexin receptor antagonist. Chronic sleep restriction significantly increased, and a dual orexin receptor antagonist decreased, amyloid-beta plaque formation in amyloid precursor protein transgenic mice. Thus, Kang et al. (2009) concluded that the sleep-wake cycle and orexin play a role in the pathogenesis of Alzheimer disease.
Amino-terminally truncated, pyroglutamylated (pE) forms of amyloid-beta are strongly associated with Alzheimer disease, are more toxic than amyloid-beta(1-42) and amyloid-beta(1-40), and have been proposed as initiators of Alzheimer disease pathogenesis. Nussbaum et al. (2012) reported a mechanism by which pE-amyloid-beta may trigger Alzheimer disease. Amyloid-beta-3(pE)-42 co-oligomerizes with excess amyloid-beta(1-42) to form metastable low-n oligomers (LNOs) that are structurally distinct and far more cytotoxic to cultured neurons than comparable LNOs made from amyloid-beta(1-42) alone. Tau is required for cytotoxicity, and LNOs comprising 5% amyloid-beta-3(pE)-42 plus 95% amyloid-beta(1-42) (5% pE-amyloid-beta) seed new cytotoxic LNOs through multiple serial dilutions into amyloid-beta(1-42) monomers in the absence of additional amyloid-beta-3(pE)-42. LNOs isolated from human Alzheimer disease brain contained amyloid-beta-3(pE)-42, and enhanced amyloid-beta-3(pE)-42 formation in mice triggered neuron loss and gliosis at 3 months, but not in a tau-null background. Nussbaum et al. (2012) concluded that amyloid-beta-3(pE)-42 confers tau-dependent neuronal death and causes template-induced misfolding of amyloid-beta(1-42) into structurally distinct LNOs that propagate by a prion-like mechanism. Nussbaum et al. (2012) concluded that their results raised the possibility that amyloid-beta-3(pE)-42 acts similarly at a primary step in Alzheimer disease pathogenesis.
Amyloid-beta toxicity in Alzheimer disease is considered to be mediated by phosphorylated tau protein. In contrast, Ittner et al. (2016) found that, at least in early disease, site-specific phosphorylation of tau inhibited amyloid-beta toxicity. This specific tau phosphorylation was mediated by the neuronal p38 mitogen-activated protein kinase p38-gamma (602399) and interfered with postsynaptic excitotoxic signaling complexes engaged by amyloid-beta. Accordingly, depletion of p38-gamma exacerbated neuronal circuit aberrations, cognitive deficits, and premature lethality in a mouse model of Alzheimer disease, whereas increasing the activity of p38-gamma abolished these deficits. Furthermore, mimicking site-specific tau phosphorylation alleviated amyloid-beta-induced neuronal death and offered protection from excitotoxicity. Ittner et al. (2016) concluded that their work provided insights into postsynaptic processes in Alzheimer disease pathogenesis and challenged a purely pathogenic role of tau phosphorylation in neuronal toxicity.
Cerebral Amyloid Angiopathy
In 2 patients with hereditary cerebral hemorrhage with amyloidosis of the Dutch type (HCHWAD; 605714), Levy et al. (1990) identified a mutation in the APP gene (E693Q; 104760.0001). The change is referred to as E22Q in the processed beta-amyloid peptide.
Grabowski et al. (2001) noted that the APP mutations associated with severe cerebral amyloid angiopathy (CAA) all occur within the region coding for beta-amyloid, particularly residues 21-23.
In 2 brothers from Iowa with autosomal dominant cerebral amyloid angiopathy (605714), Grabowski et al. (2001) identified a mutation in the APP gene (D694N; 104760.0016). This corresponds to residue D23N of the beta-amyloid peptide. Neither brother had symptomatic hemorrhagic stroke. Neuropathologic examination of the proband revealed severe cerebral amyloid angiopathy, widespread neurofibrillary tangles, and unusually extensive distribution of beta-amyloid-40 in plaques.
Familial Early-Onset Alzheimer Disease 1
In affected members of 2 families with early-onset Alzheimer disease-1 (104300), Goate et al. (1991) identified a heterozygous mutation in the APP gene (V717I; 104760.0002).
In a multicenter, multifaceted study of familial and sporadic Alzheimer disease, Tanzi et al. (1992) concluded that APP gene mutations account for a very small portion of familial Alzheimer disease (FAD). In a similar large study of AD, Kamino et al. (1992) also concluded that APP mutations account for AD in only a small fraction of FAD kindreds.
In affected members of 5 of 31 families with early-onset AD, Raux et al. (2005) identified mutations in the APP gene. Four of the families had the V717I mutation. The mean age at disease onset in APP mutation carriers was 51.2 years. Combined with earlier studies, Raux et al. (2005) estimated that 16% of early-onset AD is attributable to mutations in the APP gene.
Late-Onset Alzheimer Disease
Genetic variations in promoter sequences that alter gene expression play a prominent role in increasing susceptibility to complex diseases. Also, expression levels of APP are essentially regulated by its core promoter and 5-prime upstream regulatory region and correlate with amyloid beta levels in Alzheimer disease brains. Theuns et al. (2006) systematically sequenced the proximal promoter (-760/+204) and 2 functional distal regions of APP in 2 independent AD series with onset ages at 70 years or greater and identified 8 novel sequence variants. Three mutations identified only in patients with AD showed, in vitro, a nearly 2-fold neuron-specific increase in APP transcriptional activity, similar to what is expected from triplication of APP in Down syndrome. These mutations either abolished or created transcription factor binding sites involved in the development and differentiation of neuronal systems. Two of these clustered in the 200-bp region of the APP promoter that showed the highest degree of species conservation. The study provided evidence that APP promoter mutations that significantly increase APP levels are associated with AD.
Guyant-Marechal et al. (2007) found a significant association between a -3102G/C SNP (rs463946) in the 5-prime region of the APP gene and AD among 427 French patients with late-onset AD. The association was replicated in a second sample of 502 AD cases. The C allele was protective (odds ratio of 0.42; p = 5 x 10(-4)).
Lee et al. (2018) described recombination of the APP gene in normal and Alzheimer disease neurons occurring mosaically as thousands of variant 'genomic cDNAs' (gencDNAs). Neurons from individuals with sporadic Alzheimer disease showed increased gencDNA diversity, including 11 mutations associated with familial Alzheimer disease that were absent from healthy neurons.
Studies on Mutant APP Proteins
Suzuki et al. (1994) found that 3 mutations found at residue 717 in the APP gene familial Alzheimer disease, V717I, V717F (104760.0003), and V717G (104760.0004), were consistently associated with a 1.5- to 1.9-fold increase in the percentage of longer beta-amyloid fragments generated, and that the longer fragments formed insoluble amyloid fibrils more rapidly than did the shorter ones.
Yamatsuji et al. (1996) demonstrated that expression of any of the 3 APP mutations involving residue 717 (V717I, V717F, and V717G) induced nucleosomal DNA fragmentation in cultured neuronal cells. Induction of DNA fragmentation required the cytoplasmic domain of the mutants and appeared to be mediated by heterotrimeric guanosine triphosphate-binding proteins (G proteins).
In primary murine neuronal cultures, De Jonghe et al. (2001) compared the effect on APP processing of a series of APP mutations resulting in AD located in close proximity to the gamma-secretase cleavage site. All mutations tested affected gamma-secretase cleavage, causing an increased relative ratio of amyloid beta-42 to amyloid beta-40. The authors demonstrated an inverse correlation between these ratios and the age at onset of the disease in the different families.
Fibrillar aggregates that are closely similar to those associated with clinical amyloidoses can be formed in vitro from proteins not connected with these diseases, including the SH3 domain from bovine phosphatidyl-inositol-3-prime-kinase and the N-terminal domain of E. coli HypF protein. Bucciantini et al. (2002) showed that species formed early in the aggregation of these nondisease-associated proteins are inherently highly cytotoxic, providing added evidence that avoidance of protein aggregation is crucial for the preservation of biologic function.
Lashuel et al. (2002) demonstrated that mutant amyloid proteins associated with familial Alzheimer and Parkinson diseases (168600) formed morphologically indistinguishable annular protofibrils that resemble a class of pore-forming bacterial toxins, suggesting that inappropriate membrane permeabilization might be the cause of cell dysfunction and even cell death in amyloid diseases. The A30P (163890.0002) and A53T (163890.0001) alpha-synuclein mutations associated with Parkinson disease both promoted protofibril formation in vitro relative to wildtype alpha-synuclein. Lashuel et al. (2002) examined the structural properties of A30P, A53T, and amyloid beta 'Arctic' (104760.0013) protofibrils for shared structural features that might be related to their toxicity. The protofibrils contained beta-sheet-rich oligomers comprising 20 to 25 alpha-synuclein molecules, which formed amyloid protofibrils with a pore-like morphology.
Kayed et al. (2003) produced an antibody that specifically recognized micellar amyloid beta but not soluble, low molecular weight amyloid beta or amyloid beta fibrils. The antibody also specifically recognized soluble oligomers among all other types of amyloidogenic proteins and peptides examined, indicating that they have a common structure and may share a common pathogenic mechanism. Kayed et al. (2003) showed that all of the soluble oligomers tested displayed a common conformation-dependent structure that was unique to soluble oligomers regardless of sequence. The in vitro toxicity of soluble oligomers was inhibited by oligomer-specific antibody. Soluble oligomers have a unique distribution in human Alzheimer disease brain that is distinct from that of fibrillar amyloid. Kayed et al. (2003) concluded that different types of soluble amyloid oligomers have a common structure and suggested that they share a common mechanism of toxicity.
Morelli et al. (2003) found that recombinant rat insulin-degrading enzyme (IDE; 146680) readily degraded monomeric wildtype beta-amyloid, as well as mutants proteins A21G (104760.0005), E22K (104760.0014), and D23N (104760.0016). In contrast, proteolysis of the E22Q (104760.0001) and E22G (104760.0013) mutant proteins was not as efficient, possibly related to higher beta-structures. All of the beta-amyloid variants were cleaved at residues glu3/phe4 and phe4/arg5, in addition to positions 13-15 and 18-21.
Lustbader et al. (2004) demonstrated that amyloid beta-binding alcohol dehydrogenase (ABAD; 300256) is a direct molecular link from amyloid beta to mitochondrial toxicity. They demonstrated that amyloid beta interacts with ABAD in the mitochondria of Alzheimer disease patients and transgenic mice. The crystal structure of amyloid beta-bound ABAD showed substantial deformation of the active site that prevents nicotinamide adenine dinucleotide (NAD) binding. An ABAD peptide specifically inhibited ABAD-amyloid beta interaction and suppressed amyloid beta-induced apoptosis and free radical generation in neurons. Transgenic mice overexpressing ABAD in an amyloid beta-rich environment manifested exaggerated neuronal oxidative stress and impaired memory.
By using electron microscopy and solid-state nuclear magnetic resonance measurements on fibrils formed by the 40-residue beta-amyloid peptide of Alzheimer disease, Petkova et al. (2005) showed that different fibril morphologies have different underlying molecular structures, that the predominant structure can be controlled by subtle variations in fibril growth conditions, and that both morphology and molecular structure were self-propagating when fibrils grew from preformed seeds. Different amyloid beta(1-40) fibril morphologies also had significantly different toxicities in neuronal cell cultures.
Kanekiyo et al. (2007) detected PTGDS (176803) within amyloid plaques in the brain of a human patient with late-onset AD and in mouse models of AD. In vitro studies showed that human PTGDS inhibited the aggregation of beta-amyloid fibrils in a dose-dependent manner. Ptgds-knockout mice showed acceleration of brain beta-amyloid deposition, and transgenic mice overexpressing human PTGDS showed decreased amyloid deposition, compared to wildtype. Since PTGDS is present in human CSF, Kanekiyo et al. (2007) concluded that PTGDS acts as an endogenous beta-amyloid chaperone by binding to a particular area of APP and preventing a conformational shape change from soluble to insoluble peptides. The findings suggested that quantitative or qualitative changes in PTGDS may be involved in the pathogenesis of Alzheimer disease.
Protection Against Alzheimer Disease
Jonsson et al. (2012) searched for low-frequency variants in the amyloid-beta precursor protein gene with a significant effect on the risk of Alzheimer disease by studying coding variants in APP in a set of whole-genome sequence data from 1,795 Icelanders. Jonsson et al. (2012) found a coding mutation (A673T; 104760.0023) in the APP gene that protects against Alzheimer disease and cognitive decline in the elderly without Alzheimer disease. This substitution is adjacent to the aspartyl protease beta-site in APP, and resulted in an approximately 40% reduction in the formation of amyloidogenic peptides in vitro. The strong protective effect of the A673T substitution against Alzheimer disease provided proof of principle for the hypothesis that reducing the beta-cleavage of APP may protect against the disease. Furthermore, as the A673T allele also protects against cognitive decline in the elderly without Alzheimer disease, Jonsson et al. (2012) hypothesized that the 2 may be mediated through the same or similar mechanisms.
In a review of the genetics of cerebral amyloid angiopathy, Revesz et al. (2009) noted that APP mutations localized close to the beta-secretase or gamma-secretase cleavage sites with amino acid substitutions flanking the beta-amyloid sequence result in the clinicopathologic phenotype of early-onset Alzheimer disease with parenchymal amyloid plaques. In contrast, APP mutations resulting in amino acid substitutions within residues 21 through 34 of the beta-amyloid peptide are associated with prominent cerebral amyloid arteriopathy. Examples of CAA-causing APP mutation include the Dutch (E693Q; 104760.0001), Flemish (A692G; 104760.0005), Arctic (E693G; 104760.0013), Italian (E693K; 104760.0014), Iowa (D694N; 104760.0016), and Piedmont (L705V; 104760.0019) variants. These mutations correspond to changes in residues 22, 21, 22, 22, 23, and 34 of the beta-amyloid peptide, respectively. Beta-amyloid-40 is more likely to deposit in vessel walls compared to beta-amyloid-42, which is more likely to deposit in brain parenchyma as amyloid plaques. The ratio of these 2 forms of beta-amyloid is important in the determination of vascular deposition as observed in CAA versus parenchymal deposition as observed in classic AD.
Crystal Structure
Barrett et al. (2012) showed that the amyloid precursor protein has a flexible transmembrane domain and binds cholesterol. C99 is the transmembrane carboxy-terminal domain of the amyloid precursor protein that is cleaved by gamma-secretase to release the amyloid-beta polypeptides, which are associated with Alzheimer disease. Nuclear magnetic resonance and electron paramagnetic resonance spectroscopy showed that the extracellular amino terminus of C99 includes a surface-embedded 'N-helix' followed by a short 'N-loop' connecting to the transmembrane domain. The transmembrane domain is a flexibly curved alpha-helix, making it well suited for processive cleavage by gamma-secretase. Titration of C99 reveals a binding site for cholesterol, providing mechanistic insight into how cholesterol promotes amyloidogenesis. Membrane-buried GXXXG motifs (G, Gly; X, any amino acid), which have an established role in oligomerization, were also shown to play a key role in cholesterol binding.
Cryoelectron Microscopy
Zhou et al. (2019) reported the atomic structure of human gamma-secretase in complex with a transmembrane APP fragment at 2.6-angstrom resolution. The transmembrane helix of APP closely interacts with 5 surrounding transmembrane domains of PS1 (104311), the catalytic subunit of gamma-secretase. A hybrid beta sheet, which is formed by a beta strand from APP and 2 beta strands from PS1, guides gamma-secretase to the scissile peptide bond of APP between its transmembrane and beta strand. Residues at the interface between PS1 and APP are heavily targeted by recurring mutations from Alzheimer disease patients.
Animal Models of Alzheimer Disease
Selkoe et al. (1987) used a panel of antibodies against amyloid fibrils and their constituent vascular amyloid in 5 other species of aged mammals, including monkey, orangutan, polar bear, and dog. Antibodies to the 28-amino acid peptide recognized the cortical and microvascular amyloid of all the aged mammals examined.
Games et al. (1995) generated transgenic mice that expressed high levels of human mutant APP (V717F; 104760.0003). The mice showed progressive development of many of the pathologic hallmarks of AD, including beta-amyloid deposits, neuritic plaques, synaptic loss, astrocytosis, and microgliosis.
To test whether the amyloid beta peptide in Alzheimer disease is neurotoxic, LaFerla et al. (1995) introduced a transgene, which included 1.8 kb of 5-prime flanking DNA from the mouse neurofilament-light (NF-L) gene, into mice to restrict expression of the peptide coding region of the APP gene to neuronal cells. In situ hybridization and immunostaining with beta-amyloid antibodies detected extensive transgene expression and peptide in cerebral cortex and hippocampus, both of which are severely affected in AD. There was limited expression in other areas of the brains of the transgenic mice. The study showed that expression of beta-amyloid was sufficient to induce a progressive series of changes within the brains of transgenic mice, initiating with neurodegeneration and apoptosis, followed by the activation of secondary events such as astrogliosis, and ultimately ending with spongiosis. Accompanying the cell death was the appearance of clinical features including seizures and premature death, both of which have been described in Alzheimer disease.
Citron et al. (1997) found that expression of wildtype presenilin genes PSEN1 (104311) and PSEN2 (600759) in transfected cell lines and transgenic mouse models did not alter APP levels, alpha- and beta-secretase activity, or beta-amyloid production. However, Alzheimer disease-causing mutations in the PSEN1 and PSEN2 genes caused a highly significant increase in secretion of beta-amyloid-42 in all transgenic cell lines. In particular, the PSEN2 'Volga' mutation (N141I; 600759.0001) led to a 6- to 8-fold increase in the production of total amyloid beta-42; none of the PSEN1 mutations had such a dramatic effect, suggesting an intrinsic difference in the effects of PSEN1 and PSEN2 mutations on APP processing. Transgenic mice with Psen1 mutations overproduced beta-amyloid-42 in the brain, which was detectable at 2 to 4 months of age. Citron et al. (1997) concluded that FAD-linked presenilin mutations directly or indirectly altered the level of gamma-secretase, resulting in increased proteolysis of APP at the amyloid beta-42 site and increased production of amyloid beta-42.
Gotz et al. (2001) demonstrated that injection of beta-amyloid-42 fibrils into the brains of transgenic mice with a mutation in the MAPT gene (P301L; 157140.0001) resulted in a 5-fold increase in the numbers of neurofibrillary tangles in cell bodies within the amygdala from where neurons projected to the injection sites. Gallyas silver impregnation identified neurofibrillary tangles that contained hyperphosphorylated tau. Neurofibrillary tangles were composed of twisted filaments and occurred in 6-month-old mice as early as 18 days after A-beta-42 injections. Gotz et al. (2001) concluded that their data support the hypothesis that A-beta-42 fibrils can accelerate neurofibrillary tangle formation in vivo.
Lewis et al. (2001) crossed JNPL3 transgenic mice expressing a mutant tau protein, which developed neurofibrillary tangles and progressive motor disturbance, with Tg2576 transgenic mice expressing mutant APP (K670N/M671L; 104760.0008). The resulting double-mutant (tau/APP) progeny and the Tg2576 parental strain developed amyloid beta deposits at the same age; however, relative to JNPL3 mice, the double mutants exhibited neurofibrillary tangle pathology that was substantially enhanced in the limbic system and olfactory cortex. Lewis et al. (2001) concluded that either APP or amyloid beta influences the formation of neurofibrillary tangles. The interaction between A-beta and tau pathologies in these mice supported the hypothesis that a similar interaction occurs in Alzheimer disease.
Iwata et al. (2001) found that mice with disruption of the neprilysin gene (MME; 120520), a candidate amyloid beta-degrading peptidase, had defects in the degradation of exogenously administered amyloid beta and in the metabolic suppression of endogenous amyloid beta levels. The effects were observed in a gene dose-dependent manner. The highest regional levels of amyloid beta in the neprilysin-deficient mouse brain were, in descending order, in hippocampus, cortex, thalamus/striatum, and cerebellum, correlating with the vulnerability to amyloid beta deposition in brains of humans with Alzheimer disease. Iwata et al. (2001) concluded that even partial downregulation of neprilysin activity, which could be caused by aging, can contribute to Alzheimer disease by promoting amyloid beta accumulation.
Using 3 groups of transgenic mice carrying the presenilin A246E mutation (104311.0003), the amyloid precursor protein K670N/M671L mutation, or both mutations, Dineley et al. (2002) showed that coexpression of both mutant transgenes resulted in accelerated beta-amyloid accumulation, first detected at 7 months in the cortex and hippocampus, compared to the APP or PSEN1 transgene alone. Contextual fear learning, but not cued fear learning, was impaired in mice carrying both mutations or the APP mutation, but not the PSEN1 mutation alone. The authors suggested that contextual fear learning is a hippocampus-dependent associative learning task, as opposed to cued fear learning, which involves cortical, amygdala, and sensory processing. The impairment manifested at 5 months of age, preceding detectable plaque deposition, and worsened with age. Dineley et al. (2002) also found increased levels of alpha-7 nicotinic acetylcholine receptor (118511) protein in the hippocampus, which they hypothesized contributes to disease progression via chronic activation of the ERK/MAPK cascade.
In mice with targeted deletion of the insulin-degrading enzyme (IDE; 146680) gene, Farris et al. (2003) found a greater than 50% decrease in amyloid beta degradation in both membrane fractions and primary neuronal cultures, as well as a similar deficit in insulin degradation in liver. The Ide-null mice showed increased cerebral accumulation of endogenous amyloid beta, and had hyperinsulinemia and glucose intolerance (see 176730), hallmarks of type II diabetes (125853). Moreover, the mice had elevated levels of the intracellular signaling domain of the beta-amyloid precursor protein, which had recently been found to be degraded by IDE in vitro. Farris et al. (2003) concluded that, together with emerging genetic evidence, their in vivo findings suggest that IDE hypofunction may underlie or contribute to some forms of AD and type II diabetes and provide a mechanism for the recognized association among hyperinsulinemia, diabetes, and AD.
Lehman et al. (2003) transferred a mutant human APP YAC transgene to 3 inbred mouse strains. Despite similar levels of holo-APP expression in the congenic strains, the levels of APP C-terminal fragments as well as brain and plasma beta-amyloid in young animals varied by genetic background. Age-dependent beta-amyloid deposition in the APP YAC transgenic model was dramatically altered depending on the congenic strain examined. Lehman et al. (2003) concluded that APP processing, beta-amyloid metabolism, and beta-amyloid deposition are regulated by genetic background.
In Drosophila, Iijima et al. (2004) found that overexpression of human A-beta-42 led to the formation of diffuse amyloid deposits, age-dependent learning defects, and extensive neurodegeneration. In contrast, overexpression of human A-beta-40 caused only age-dependent learning defects, but did not lead to the formation of amyloid deposits or neurodegeneration. These results strongly suggested that accumulation of A-beta-42 in the brain is sufficient to cause behavioral deficits and neurodegeneration.
Phenotypes produced by expression of human APP transgenes vary depending on the genetic background of the mouse. To identify genes that determine susceptibility or resistance to APP, Krezowski et al. (2004) analyzed crosses involving FVB/NCr and 129S6-Tg2576 mice that overexpressed the 'Swedish' mutant K670N/M671L. APP transgene-positive F1 mice were resistant to the lethal effects of APP overexpression, so FVBxF1 backcross and F2 intercross offspring were produced. Analysis of age of death as a quantitative trait revealed significant linkage to loci on proximal chromosome 14 and on chromosome 9; 129S6 alleles protected against the lethal effects of APP. Within the chromosome 14 interval are segments homologous to regions on human chromosome 10 that have been linked to late-onset Alzheimer disease or to levels of A-beta peptide in plasma. However, analysis of plasma A-beta peptide concentrations at 6 weeks in backcross offspring produced no significant linkage. Similarly, elevation of human A-beta peptide concentrations by expression of mutant presenilin transgenes did not increase the proportion of mice dying prematurely. Krezowski et al. (2004) suggested that early death may reflect effects of APP or fragments other than A-beta.
Yue et al. (2005) generated APP23 mice, a mouse model of AD, that were also estrogen-deficient due to heterozygous disruption of the aromatase gene (CYP19A1; 107910). Compared to control APP23 mice with normal aromatase activity, the estrogen-deficient mice showed decreased brain estrogen, earlier onset of plaques, and increased brain beta-amyloid deposition. Microglia cultures from these mice showed impaired beta-amyloid clearance. In contrast, ovariectomized APP23 mice had normal brain estrogen levels and showed plaque pathology similar to control APP23 mice. In addition, Yue et al. (2005) found that postmortem brain tissue from 10 female AD patients showed 60% and 85% decreased levels of total and free estrogen, respectively, as well as decreased levels of aromatase mRNA compared to 10 female controls. However, serum estrogen levels were not different between the 2 groups. Yue et al. (2005) concluded that reduced brain estrogen production may be a risk factor for developing AD neuropathology.
APP is cleaved intracytoplasmically at asp664 by caspases, liberating a cytotoxic C-terminal peptide, APP-C31. In mice carrying the V717F and K670N/M671L mutations, Galvan et al. (2006) introduced the asp664-to-ala (D664A) mutation that abolishes the caspase cleavage site. These mice developed beta-amyloid plaques but did not develop subsequent synaptic loss, astrogliosis, dentate gyral atrophy, or behavioral abnormalities compared to double-mutant mice without the D664A change. The findings suggested that asp664 plays a role in the generation of AD-like pathophysiologic changes.
Reddy et al. (2004) investigated the APP Tg2576 transgenic mouse model for gene expression profiles at 3 stages of disease progression. The authors measured mRNA levels in 11,283 cDNA clones from the cerebral cortex of Tg2576 mice and age-matched wildtype mice at each of the 3 time points. Genes related to mitochondrial energy metabolism and apoptosis were upregulated at all 3 time points. Results from in situ hybridization of ATPase-6 (516060), heat-shock protein-86, and programmed cell death gene-8 (PDCD8; 300169) suggested that the granule cells of the hippocampal dentate gyrus and the pyramidal neurons in the hippocampus and the cerebral cortex were upregulated in Tg2576 mice compared with wildtype mice. Results from double-labeling in situ hybridization suggested that in Tg2576 mice only selective, overexpressed neurons with the mitochondrial gene ATPase-6 underwent oxidative damage. The authors suggested that mitochondrial energy metabolism may be impaired by the expression of mutant APP and/or A-beta, and that the upregulation of mitochondrial genes may be a compensatory response.
McGowan et al. (2005) demonstrated that beta-amyloid-42 is required for deposition of parenchymal and vascular amyloid plaques in a mouse model of AD that expresses beta-A-40 and beta-A-42 without APP overexpression. Mice expressing high levels of beta-A-40 specifically did not develop overt amyloid pathology, whereas mice expressing lower levels of beta-A-42 specifically accumulated insoluble beta-A-42, amyloid angiopathy, and other amyloid deposits.
Colton et al. (2006) found that Tg2576 mice on a Nos2 (163730)-null background developed pathologic hyperphosphorylation of tau with aggregate formation in the brain. Lack of Nos2 increased insoluble APP levels, neuronal degeneration, caspase-3 (CASP3; 600636) activation, and tau cleavage, suggesting that nitric oxide may act at a junction point between the 2 main pathologies that characterize AD.
El Khoury et al. (2007) found that Ccr2 (601627)-deficient Tg2576 mice demonstrated increased mortality at age 8 weeks compared to control Tg2576 mice. Ccr2 -/- Tg2576 mice had significantly increased brain beta-amyloid levels and significantly decreased levels of microglia compared to brains of control Tg2576 mice. Ccr2 -/- mononuclear phagocytes showed normal activity and proliferation, but impaired migration in response to beta-amyloid deposition. The findings indicated that Ccr2-dependent microglial accumulation plays a protective role in Alzheimer disease by mediating beta-amyloid clearance.
Meyer-Luehmann et al. (2006) reported that intracerebral injection of diluted amyloid beta-containing brain extracts from humans with Alzheimer disease or APP transgenic mice induced cerebral beta-amyloidosis and associated pathology in APP transgenic mice in a time- and concentration-dependent manner. The seeding activity of brain extracts was reduced or abolished by amyloid beta immunodepletion, protein denaturation, or by amyloid beta immunization of the host. Meyer-Luehmann et al. (2006) found that the phenotype of the exogenously induced amyloidosis was dependent on both the host and the source of the agent, suggesting the existence of polymorphic amyloid beta strains with varying biologic activities reminiscent of prion strains.
In rat neuroblastoma cells and brain, Fombonne et al. (2009) demonstrated that APP interacted directly with the nerve growth factor receptor (NGFR; 162010), which can mediate neuronal cell death. The interaction could be modified by the ligands NGF and beta-amyloid. In addition, APP and NGFR could affect the processing of each other, and coexpression of the 2 could trigger cell death. The results provided a mechanism for selective death of basal forebrain cholinergic neurons in Alzheimer disease, since these neurons express NGFR.
Hassan et al. (2009) used a transgenic C. elegans Alzheimer disease model to identify cellular responses to proteotoxicity resulting from expression of the human beta-amyloid peptide. C. elegans arsenite-inducible protein-1 (Aip1) was upregulated in A-beta-expressing animals. Overexpression of Aip1 protected against, while RNAi knockdown of Aip1 exacerbated, A-beta toxicity. Aip1 overexpression also reduced accumulation of A-beta in this model, which is consistent with Aip1 enhancing protein degradation. Transgenic expression of human Aip1 homologs AIRAPL (ZFAND2B), but not AIRAP (ZFAND2A; 610699) suppressed A-beta toxicity in C. elegans. The Aip1 farnesylation site (which is absent from AIRAP) is essential for an Aip1 prolongevity function, and an Aip1 mutant lacking the predicted farnesylation site failed to protect against A-beta toxicity. Hassan et al. (2009) proposed that Aip1 may play a role in the regulation of protein turnover and protection against A-beta toxicity and suggested that AIRAPL may be the functional mammalian homolog of C. elegans Aip1.
Tong et al. (2010) generated transgenic mice that overexpressed human COL25A1 (610004) and observed accumulation of beta-amyloid in the brain associated with increased Bace1 (604252) levels and increased levels of Cdk5r1 (603460), which activates Cdk5 (123831). These changes were associated with loss of synaptophysin (SYP; 313475), astrocyte activation, and behavioral abnormalities. The findings suggested that COL25A1 may play a role in the pathogenesis of Alzheimer disease.
Burns et al. (2009) tested whether the ubiquitin ligase activity of parkin (PARK2; 602544) could lead to reduction of intracellular human A-beta-42 fragments. Lentiviral constructs encoding either human parkin or human A-beta-42 were used to infect human neuroblastoma M17 cells. Parkin expression resulted in reduction of intracellular human A-beta-42 levels and protected against its toxicity in M17 cells. Coinjection of lentiviral constructs into control rat primary motor cortex demonstrated that parkin coexpression reduced human A-beta-42 levels and A-beta-42-induced neuronal degeneration in vivo. Parkin increased proteasomal activity, and proteasomal inhibition blocked the effects of parkin on reducing A-beta-42 levels. Incubation of A-beta-42 cell lysates with ubiquitin, in the presence of parkin, demonstrated the generation of A-beta/ubiquitin complexes. Burns et al. (2009) concluded that parkin promotes ubiquitination and proteasomal degradation of intracellular A-beta-42 and demonstrated a protective effect in neurodegenerative diseases with A-beta deposits.
The intracerebral injection of beta-amyloid-containing brain extracts can induce cerebral beta-amyloidosis and associated pathologies in susceptible hosts. Eisele et al. (2010) found that intraperitoneal inoculation with beta-amyloid-rich extracts induced beta-amyloidosis in the brains of beta-amyloid precursor protein transgenic mice after prolonged incubation times. Eisele et al. (2010) estimated that intraperitoneal inoculation with 1,000 times as much amyloid-beta take 2 to 5 times longer to induce cerebral amyloidosis than do intracerebral inoculations.
Using transgenic Drosophila expressing human A-beta-42 and tau (MAPT; 157140), Iijima et al. (2010) showed that tau phosphorylation at ser262 played a critical role in A-beta-42-induced tau toxicity. Coexpression of A-beta-42 increased tau phosphorylation at AD-related sites including ser262 and enhanced tau-induced neurodegeneration. In contrast, formation of either sarkosyl-insoluble tau or paired helical filaments was not induced by A-beta-42. Coexpression of A-beta-42 and tau carrying the nonphosphorylatable ser262ala mutation did not cause neurodegeneration, suggesting that the ser262 phosphorylation site is required for the pathogenic interaction between A-beta-42 and tau. DNA damage-activated checkpoint kinase-2 (CHK2; 604373) phosphorylates tau at ser262 and enhances tau toxicity in a transgenic Drosophila model (Iijima-Ando et al., 2010). Exacerbation of A-beta-42-induced neuronal dysfunction by blocking tumor suppressor p53 (191170), a key transcription factor for the induction of DNA repair genes, in neurons suggested that induction of a DNA repair response is protective against A-beta-42 toxicity. The authors concluded that tau phosphorylation at ser262 is crucial for A-beta-42-induced tau toxicity in vivo, and they suggested a model of AD progression in which activation of DNA repair pathways is protective against A-beta-42 toxicity but may trigger tau phosphorylation and toxicity in AD pathogenesis.
Therapeutic Strategies for Alzheimer Disease
Meziane et al. (1998) reported memory-enhancing effects of secreted forms of APP in normal and amnestic (forgetful) mice. When administered intracerebroventricularly into mice performing various learning tasks involving either short-term or long-term memory, the APP751 and APP695 secreted forms of APP had potent memory-enhancing effects and blocked learning deficits induced by scopolamine. The memory-enhancing effects of secreted APP were observed over a wide range of very low doses, blocked by anti-APP antisera, and observed when secreted APP was administered either after the first training session in a visual discrimination or a lever-press learning task or before the acquisition trial in an object recognition task. There was no effect on motor performance or exploratory activity. The findings suggested that the memory-enhancing effect does not require the Kunitz protease inhibitor domain. Sisodia and Gallagher (1998) reviewed what had been learned about APP function from in vitro studies and studies in knockout mice. Several lines of evidence suggested that APP may play a role in synapse formation and maintenance. They commented that the studies by Meziane et al. (1998) suggested that secretory APP alters the function of cholinergic neurons or their targets because impairment caused by administration of scopolamine was alleviated by concurrent peptide treatment.
Schenk et al. (1999) found that transgenic mice overexpressing the AD-related V717F mutation (104760.0003) and immunized with beta-amyloid-42 at age 6 weeks did not develop beta-amyloid plaques, neuritic dystrophy, or astrogliosis. Immunization of older transgenic animals at age 11 months also markedly reduced the extent and progression of these AD-like neuropathologies. Animals that began treatment at 11 months of age showed greater than 99% reduction of amyloid beta-42 burden at 18 months of age compared with untreated littermates. In addition, the absence of neuritic and gliotic changes and astrogliosis indicated that the immunized mice never developed the neurodegenerative lesions that typify the progression of AD-like pathology. Subsequent studies showed that the production of beta-amyloid was unaffected by immunization, suggesting that immunization either prevented deposition and/or enhanced the clearance of amyloid beta from the brain.
Janus et al. (2000) showed that amyloid beta immunization of TgCRND8 transgenic mice (with the K670N/M671L; 104760.0008 and V717F mutations) reduced both deposition of cerebral fibrillar amyloid beta and cognitive dysfunction without altering total levels of amyloid beta in the brain. The authors concluded that an approximately 50% reduction in dense-cored amyloid beta plaques is sufficient to affect cognition, and that vaccination may modulate the activity/abundance of a small subpopulation of especially toxic amyloid beta species.
In several transgenic mouse models of AD, including a PSEN1 mutant (Duff et al., 1996), an APP mutant (Hsiao et al., 1996), and a double transgenic that contained both mutations, Morgan et al. (2000) showed that vaccination with amyloid beta offered protection from the learning and age-related memory deficits that normally occurred in these mouse models. During testing for potential deleterious effects of the vaccine, all mice performed superbly on the radial-arm water-maze test of working memory. Later, at an age when untreated transgenic mice showed memory deficits, the amyloid beta-vaccinated transgenic mice showed cognitive performance superior to that of the control transgenic mice.
Weggen et al. (2001) reported that the nonsteroidal antiinflammatory drugs (NSAIDS) ibuprofen, indomethacin, and sulindac preferentially decreased the high amyloidogenic amyloid beta-42 peptide produced from a variety of cultured cells by as much as 80%. This effect was not seen in all NSAIDs and seemed not to be mediated by inhibition of cyclooxygenase activity, the principal pharmacologic target of NSAIDs. Weggen et al. (2001) also demonstrated that short-term administration of ibuprofen to mice that produce APP lowered their brain levels of amyloid beta-42. In cultured cells, the decrease in amyloid beta-42 secretion was accompanied by an increase in the amyloid beta(1-38) isoform, indicating that NSAIDs subtly alter gamma-secretase activity without significantly perturbing other APP processing pathways or Notch cleavage. Weggen et al. (2001) concluded that NSAIDs directly affect amyloid pathology in the brain by reducing amyloid beta-42 peptide levels independently of COX activity. Lleo et al. (2004) used a fluorescence resonance energy transfer-based assay (fluorescence lifetime imaging; FLIM) to analyze how NSAIDs influence APP-presenilin-1 interactions. In vitro and in vivo, ibuprofen, indomethacin, or flurbiprofen, but not aspirin or naproxen, had an allosteric effect on the conformation of PSEN1, which changed the gamma-secretase activity on APP to increase production of the shorter beta-38 cleavage product.
DeMattos et al. (2002) demonstrated that, as in humans, baseline plasma amyloid beta levels did not correlate with brain amyloid burden in mouse models of AD. However, after peripheral administration of a monoclonal antibody to amyloid beta (m266), they observed a rapid increase in plasma amyloid beta, and the magnitude of this increase was highly correlated with amyloid burden in the hippocampus and cortex. DeMattos et al. (2002) suggested that this method may be useful for quantifying brain amyloid burden in patients at risk for or those who have been diagnosed with Alzheimer disease. Dodart et al. (2002) found that passive immunization with the same anti-A-beta monoclonal antibody could very rapidly reverse memory impairment in certain learning and memory tasks in the mouse model of AD, owing perhaps to enhanced peripheral clearance and/or sequestration of a soluble brain A-beta species.
Pfeifer et al. (2002) studied passive immunization of APP23 transgenic mice, a model that exhibits the age-related development of amyloid plaques and neurodegeneration as well as cerebral amyloid angiopathy similar to that observed in the human AD brain. Consistent with earlier reports, Pfeifer et al. (2002) found that passive amyloid beta immunization resulted in a significant reduction of mainly diffuse amyloid. However, it also induced an increase in cerebral microhemorrhages associated with amyloid-laden vessels, suggesting a possible link to the neuroinflammatory complications of amyloid beta immunization seen in a human trial (Schenk, 2002).
In a transgenic mouse model of Alzheimer disease with mutations in the App gene, Cherny et al. (2001) found that treatment with the copper and zinc chelator clioquinol resulted in a decrease in brain beta-amyloid deposition, an increase in soluble brain beta-amyloid, and in stabilization of general health and body weight parameters. In vitro studies of human AD brains showed that clioquinol caused an increase in soluble beta-amyloid liberated from beta-amyloid deposits.
Walsh et al. (2002) reported that natural oligomers of human amyloid beta are formed soon after generation of the peptide within specific intracellular vesicles and are subsequently secreted from the cell. Cerebral microinjection of cell medium containing these oligomers and abundant amyloid beta monomers but no amyloid fibrils markedly inhibited hippocampal long-term potentiation in rats in vivo. Immunodepletion from the medium of all amyloid beta species completely abrogated this effect. Pretreatment of the medium with insulin-degrading enzyme, which degrades amyloid beta monomers but not oligomers, did not prevent the inhibition of long-term potentiation. Walsh et al. (2002) concluded that amyloid beta oligomers, in the absence of monomers and amyloid fibrils, disrupted synaptic plasticity in vivo at concentrations found in human brain and cerebrospinal fluid. Finally, treatment of cells with gamma-secretase inhibitors prevented oligomer formation at doses that allowed appreciable monomer production, and such medium no longer disrupted long-term potentiation, indicating that synaptotoxic amyloid beta oligomers can be targeted therapeutically.
Wyss-Coray et al. (1997) found that aged transgenic mice with increased astrocytic expression of transforming growth factor beta-1 (TGFB1; 190180) developed increased beta-amyloid deposition in cerebral blood vessels and meninges. Cerebral vessel amyloid deposition was further increased in transgenic mice overexpressing human APP (Games et al., 1995), similar to the vascular changes seen in patients with Alzheimer disease and cerebral amyloid angiopathy. Postmortem analysis of 15 AD brains showed increased TGFB1 immunoreactivity and increased TGFB1 mRNA, which correlated with beta-amyloid deposition in damaged cerebral blood vessels of patients with AD and cerebral amyloid angiopathy compared to AD patients without cerebral amyloid angiopathy or normal controls. Wyss-Coray et al. (1997) concluded that glial overexpression of TGFB1 may promote the deposition of cerebral vascular beta-amyloid in AD-related amyloidosis.
Wyss-Coray et al. (2001) demonstrated that a modest increase in astroglial TGFB1 production in aged transgenic mice expressing the human APP gene resulted in a 3-fold reduction in the number of parenchymal amyloid plaques, a 50% reduction in the overall amyloid beta load in the hippocampus and neocortex, and a decrease in the number of dystrophic neurites. In mice expressing human APP and TGFB1, amyloid beta accumulated substantially in cerebral blood vessels, but not in parenchymal plaques. In human AD cases, amyloid beta immunoreactivity associated with parenchymal plaques was inversely correlated with amyloid beta in blood vessels and cortical TGFB1 mRNA levels. The reduction of parenchymal plaques in APP/TGFB1 mice was associated with a strong activation of microglia and an increase in inflammatory mediators. Wyss-Coray et al. (2001) concluded that TGFB1 is an important modifier of amyloid deposition in vivo and suggested that TGFB1 might promote microglial processes that inhibit the accumulation of amyloid beta in the brain parenchyma.
Tesseur et al. (2006) found significantly decreased levels of TGFBR2 (190182) in human AD brain compared to controls; the decrease was correlated with pathologic hallmarks of the disease. Similar decreases were not seen in brain extracts from patients with other forms of dementia. In a mouse model of AD, reduced neuronal TGFBR2 signaling resulted in accelerated age-dependent neurodegeneration and promoted beta-amyloid accumulation and dendritic loss. Reduced TGFBR2 signaling in neuroblastoma cell cultures resulted in increased levels of secreted beta-amyloid and soluble APP. The findings suggested a role for TGFB1 signaling in the pathogenesis of AD.
Puglielli et al. (2001) found that beta-amyloid production was regulated by intracellular cholesterol compartmentation. Specifically, cytoplasmic cholesteryl esters, formed by acyl-CoA:cholesterol acyltransferase (SOAT1; 102642), were correlated with beta-amyloid production. In vitro studies showed that inhibition of SOAT1 reduced beta-amyloid generation, and the authors concluded that SOAT1 indirectly modulates beta-amyloid generation by controlling the equilibrium between free cholesterol and cytoplasmic cholesteryl esters. Hutter-Paier et al. (2004) found that inhibition of SOAT1 significantly reduced brain amyloid plaques, insoluble amyloid levels, and brain cholesteryl esters in a transgenic mouse model of AD generated by mutations in the APP gene. Spatial learning in the transgenic mice was slightly improved and correlated with decreased beta-amyloid levels.
Netzer et al. (2003) found that imatinib mesylate (Gleevec), an Abl kinase (189980) inhibitor, potently reduced beta-amyloid production in cultured mouse neuroblastoma cells and guinea pig brain without affecting the gamma-secretase-mediated cleavage of Notch1 (190198). The effects of Gleevec were also seen in cells from Abl-null mice, indicating that the effect did not involve Abl kinase.
Zhou et al. (2003) found that Rho (see 165390) and its effector Rock1 (601702) preferentially regulated the amount of A-beta(42) produced in vitro and that only those NSAIDs effective as Rho inhibitors lowered A-beta(42). Administration of a selective Rock inhibitor also preferentially lowered brain levels of A-beta(42) in a transgenic mouse model of Alzheimer disease. Zhou et al. (2003) concluded that the Rho-Rock pathway may regulate amyloid precursor protein processing, and a subset of NSAIDs can reduce A-beta(42) through inhibition of Rho activity.
Phiel et al. (2003) showed that glycogen synthase kinase-3-alpha (GSK3A; 606784) is required for maximal production of the beta-amyloid-40 and -42 peptides generated from APP by presenilin-dependent gamma-secretase cleavage. In vitro, lithium, a GSK3A inhibitor, blocked the production of the beta-amyloid peptides by interfering with the gamma-secretase step. In mice expressing familial AD-associated mutations in APP and PSEN1, lithium reduced the levels of beta-amyloid peptides. Phiel et al. (2003) noted that GSK3A also phosphorylates the tau protein (MAPT; 157140), the principal component of neurofibrillary tangles in AD, and suggested that inhibition of GSK3A may offer a new therapeutic approach to AD.
Roberds et al. (2001) found that primary cortical cultures from Bace-null mice produced much less amyloid beta from APP, suggesting that the BACE gene may be a specific therapeutic target for treatment of AD. Ohno et al. (2004) generated bigenic BACE knockout mice overexpressing a mutant APP protein (Tg2576). Compared to Tg2576 mice, the bigenic BACE -/-*Tg2576+ mice performed significantly better on hippocampus-dependent learning and recognition and were rescued to wildtype performance. The bigenic mice had increased hippocampal neuronal cholinergic stimulation compared to the Tg2576 mice. The behavioral and electrophysiologic rescue of deficits in the bigenic mice correlated with a dramatic reduction of cerebral amyloid beta-40 and amyloid beta-42 levels, and occurred before amyloid deposition in the Tg2576 mice. Ohno et al. (2004) concluded that lower beta-amyloid levels are beneficial for AD-associated memory impairments and suggested BACE as a therapeutic target.
Leissring et al. (2003) found that developmentally delayed, neuron-specific overexpression of insulin-degrading enzyme or the beta-amyloid-degrading endopeptidase neprilysin (MME; 120520) in mice significantly reduced brain beta-amyloid levels, retarded or prevented amyloid plaque formation and its associated cytopathology, and rescued the premature lethality in APP transgenic mice. They concluded that chronic upregulation of beta-amyloid-degrading proteases may combat Alzheimer-type pathology in vivo.
Postina et al. (2004) found that moderate neuronal overexpression of human ADAM10 (602192) in mice carrying the human V717 mutation (104760.0002) increased secretion of the neurotrophic soluble alpha-secretase-released N-terminal APP domain, reduced formation of amyloid beta peptides, and prevented their deposition in plaques. Functionally, impaired long-term potentiation and cognitive deficits were alleviated. Expression of mutant catalytically-inactive ADAM10 in mice carrying a human APP mutation led to an enhancement of the number and size of amyloid plaques in the brains of such mice.
Lazarov et al. (2005) found that exposure of transgenic mice coexpressing FAD-linked APP and PSEN1 variants to an enriched environment composed of large cages, running wheels, colored tunnels, toys, and chewable material resulted in pronounced reductions in cerebral beta-amyloid levels and amyloid deposits compared with animals raised under standard housing conditions. The enzymatic activity of neprilysin was elevated in the brains of enriched mice and inversely correlated with amyloid burden. Moreover, DNA microarray analysis revealed selective upregulation in levels of transcripts encoded by genes associated with learning and memory, vasculogenesis, neurogenesis, cell survival pathways, beta-amyloid sequestration, and prostaglandin synthesis. These studies provided evidence that environmental enrichment leads to reductions in steady-state levels of cerebral beta-amyloid peptides and amyloid deposition and selective upregulation in levels of specific transcripts in brains of transgenic mice.
Saito et al. (2005) found that somatostatin (SST; 182450) modulated the proteolytic degradation of beta-amyloid catalyzed by neprilysin both in vitro and in vivo. Primary cortical neurons treated with somatostatin showed an upregulation of neprilysin activity and a reduction in A-beta-42. Sst-null mice showed a 1.5-fold increase in hippocampal A-beta-42, but not A-beta-40. Saito et al. (2005) noted that expression of somatostatin in the brain declines with normal aging, and postulated that a similar decrease in neprilysin activity with gradual accumulation of toxic beta-amyloid may underlie late-onset AD.
Dodart et al. (2005) generated mice carrying the APP V717F mutation (104760.0003) and found that intracerebral hippocampal delivery of the human ApoE E4 gene in V717F-mutant mice that lacked mouse Apoe resulted in increased beta-amyloid deposition compared to similar mice that received human ApoE E3 or E4. In V717F-mutant mice expressing mouse Apoe, administration of human ApoE E4 did not result in increased beta-amyloid burden, and administration of human ApoE E2 resulted in decreased beta-amyloid burden, reflecting the dominant effect of the human E2 isoform. Dodart et al. (2005) noted that the findings were consistent with ApoE isoform-dependent human neuropathologic findings. However, the lentiviral vectors used to deliver ApoE isoforms appeared to result in a loss of hippocampal granule neurons, suggesting a neurotoxic effect.
Choi et al. (2006) found that doubly transgenic mice expressing the V717F mutation and overexpressing PRKCE (176975) had decreased amyloid plaques, plaque-associated neuritic dystrophy, and reactive astrocytosis compared to mice only expressing the V717F mutation. There was no evidence for altered APP cleavage in the doubly transgenic mice; instead, overexpression of PRKCE increased the activity of endothelin-converting enzyme (ECE1; 600423), which degrades beta-amyloid.
In a transgenic mouse model of AD, Mueller-Steiner et al. (2006) found that lentiviral transfection of cathepsin B (CTSB; 116810) into the hippocampus reduced the relative abundance of beta-amyloid-42 through proteolysis at the C terminus. Genetic inactivation of cathepsin B resulted in increased beta-amyloid-42 and worsening amyloid plaque deposition. Immunohistochemical studies showed that Ctsb accumulated preferentially in mature amyloid plaques in mouse brain and was associated with neurons, astrocytes, and microglia. The proteolytic activities of Ctsb were induced by beta-amyloid-42 in young and middle-aged mice, but not old mice. The findings indicated that Ctsb likely fulfills antiamyloidogenic and neuroprotective functions.
Khan et al. (2007) reported that doubly transgenic mice expressing an AD-related APP mutation and overexpressing mouse neuroglobin (NGB; 605304) showed decreased beta-amyloid deposits, decreased levels of beta-amyloid-40 and -42, and improved behavioral performance compared to AD mice not overexpressing Ngb. Mutant APP- and NMDA-induced neuronal death was associated with membrane polarization and mitochondrial aggregation, which were inhibited by Ngb overexpression. Khan et al. (2007) concluded that the neuroprotective role of NGB extends beyond hypoxic-ischemic protection and that NGB may also act to protect neurons from beta-amyloid toxicity and NMDA toxicity by inhibiting the formation of a death-signaling membrane complex.
Town et al. (2008) found that Tg2576 transgenic mice with targeted disruption of the TGFB1 gene showed a mitigation of Tg2576-associated hyperactivity and partial mitigation of defective spatial working memory. Doubly transgenic mice also had decreased brain parenchymal and cerebrovascular beta-amyloid deposits compared to Tg2576 mice. These findings were associated with increased infiltration of peripheral macrophages containing beta-amyloid. In vitro, cultured macrophages from doubly transgenic mice demonstrated inhibition of TGFB1-SMAD2 (601366)/SMAD3 (603109) signaling, which the authors proposed resulted in an antiinflammatory phenotype endorsing beta-amyloid phagocytosis.
Cyclophilin D (see 604486) is an integral part of the mitochondrial permeability transition pore, whose opening leads to cell death. Du et al. (2008) showed that interaction of cyclophilin D with mitochondrial amyloid-beta protein potentiates mitochondrial, neuronal, and synaptic stress. The cyclophilin D-deficient cortical mitochondria from Ppif-null mice were resistant to amyloid-beta- and calcium-induced mitochondrial swelling and permeability transition. Additionally, they had an increased calcium buffering capacity and generated fewer mitochondrial reactive oxygen species. Furthermore, the absence of cyclophilin D protected neurons from amyloid-beta- and oxidative stress-induced cell death. Notably, cyclophilin D deficiency substantially improved learning and memory and synaptic function in an Alzheimer disease mouse model and alleviated amyloid-beta-mediated reduction of long-term potentiation. Thus, Du et al. (2008) concluded that the cyclophilin-D-mediated mitochondrial permeability transition pore is directly linked to the cellular and synaptic perturbations observed in the pathogenesis of Alzheimer disease. They suggested that blockade of cyclophilin D may be a therapeutic strategy in the treatment of Alzheimer disease.
Schilling et al. (2008) found that the N-terminal pyroglutamate (pE) formation of amyloid beta is catalyzed by glutaminyl cyclase (607065) in vivo. Glutaminyl cyclase expression was upregulated in the cortices of individuals with Alzheimer disease and correlated with the appearance of pE-modified amyloid beta. Oral application of a glutaminyl cyclase inhibitor resulted in reduced amyloid beta(3(pE)-42) burden in 2 different transgenic mouse models of Alzheimer disease and in a new Drosophila model. Treatment of mice was accompanied by reductions in amyloid beta(X-40/42), diminished plaque formation and gliosis, and improved performance in context memory and spatial learning tests. Schilling et al. (2008) suggested that their observations were consistent with the hypothesis that amyloid beta(3(pE)-42) acts as a seed for amyloid beta aggregation by self-aggregation and coaggregation with amyloid beta(1-40/42). Therefore, amyloid beta(3(pE)-40/42) peptides seem to represent amyloid beta forms with exceptional potency for disturbing neuronal function. The authors suggested that the reduction of brain pE-modified amyloid beta by inhibition of glutaminyl cyclase offers a new therapeutic option for the treatment of Alzheimer disease and provides implications for other amyloidoses.
X11-beta (APBA2; 602712) is a neuronal adaptor protein that binds to the intracellular domain of amyloid precursor protein. Overexpression of X11-beta inhibits A-beta production in a number of experimental systems. Mitchell et al. (2009) reported that X11-beta-mediated reduction in cerebral A-beta was associated with normalization of both cognition and in vivo long-term potentiation in aged APPswe Tg2576 transgenic mice that model the amyloid pathology of Alzheimer disease. Overexpression of X11-beta itself had no detectable adverse effects upon mouse behavior. Mitchell et al. (2009) proposed that modulation of X11-beta function may represent a therapeutic target for A-beta-mediated neuronal dysfunction in Alzheimer disease.
Lauren et al. (2009) identified the cellular prion protein (PrP-C, 176640) as an amyloid-beta oligomer receptor by expression cloning. Amyloid-beta oligomers bind with nanomolar affinity to PrP-C, but the interaction does not require the infectious PrP-Sc conformation. Synaptic responsiveness in hippocampal slices from young adult PrP-null mice was normal, but the amyloid-beta oligomer blockade of long-term potentiation was absent. Anti-PrP antibodies prevented amyloid-beta-oligomer binding to PrP-C and rescued synaptic plasticity from oligomeric amyloid-beta in hippocampal slices. Lauren et al. (2009) concluded that PrP-C is a mediator of amyloid-beta-oligomer-induced synaptic dysfunction and that PrP-C-specific pharmaceuticals may have therapeutic potential for Alzheimer disease.
Cisse et al. (2011) showed that amyloid-beta oligomers bind to the fibronectin repeat domain of EphB2 (600997) and trigger EphB2 degradation in the proteasome. To determine the pathogenic importance of EphB2 depletions in Alzheimer disease and related models, they used lentiviral constructs to reduce or increase neuronal expression of EphB2 in memory centers of the mouse brain. In nontransgenic mice, knockdown of EphB2 mediated by short hairpin RNA reduced NMDA receptor currents and impaired long-term potentiation, which are important for memory formation, in the dentate gyrus. Increasing EphB2 expression in the dentate gyrus of human amyloid precursor protein transgenic mice reversed deficits in NMDA receptor-dependent long-term potentiation and memory impairments. Thus, Cisse et al. (2011) concluded that depletion of EphB2 is critical in amyloid-beta-induced neuronal dysfunction, and suggests that increasing EphB2 levels or function could be beneficial in Alzheimer disease.
Ahn et al. (2014) noted that fibrinogen (see 134820) is a cerebrovascular risk factor in AD that specifically binds beta-amyloid, thereby altering fibrin clot structure and delaying clot degradation. Using a high-throughput screen, they identified RU-505 as an inhibitor of the interaction between beta-amyloid and fibrinogen. RU-505 restored beta-amyloid-induced altered fibrin clot formation and degradation in vitro and inhibited vessel occlusion in AD transgenic mice. Long-term treatment with RU-505 significantly reduced vascular amyloid deposition and microgliosis in cortex and improved cognitive impairment in mouse models of AD. Ahn et al. (2014) proposed that inhibitors of the interaction between beta-amyloid and fibrinogen may be useful in AD therapy.
Other Disease Models
Affected muscle fibers in inclusion body myositis (IBM; 147421) demonstrate pathobiochemical alterations traditionally associated with neurodegenerative brain disorders such as Alzheimer disease. Accumulation of the beta-APP peptide is an early pathologic event in both Alzheimer disease and IBM; however, in the latter, it occurs predominantly intracellularly within affected myofibers. Sugarman et al. (2002) found that mice with targeted overexpression of APP in skeletal muscle developed histopathologic and clinical features characteristic of IBM, including centric nuclei, inflammation, and deficiencies in motor performance. These results were considered consistent with a pathogenic role for beta-APP mismetabolism in human IBM.
Meyer-Luehmann et al. (2008) investigated the temporal relation between plaque formation and the changes in local neuritic architecture using longitudinal in vivo multiphoton microscopy to sequentially image young APPswe/PS1d9xYFP (B6C3-YFP) transgenic mice, established by Jankowsky et al. (2001). Meyer-Luehmann et al. (2008) showed that plaques form extraordinarily quickly, over 24 hours. Within 1 to 2 days of a new plaque's appearance, microglia are activated and recruited to the site. Progressive neuritic changes ensue, leading to increasingly dysmorphic neurites over the next days to weeks. Meyer-Luehmann et al. (2008) concluded that their data established plaques as a critical mediator of neuritic pathology.
Loane et al. (2009) found that mice exposed to traumatic brain injury (TBI) via controlled cortical impact developed accumulations of endogenous beta-amyloid-40 within 1 day. The beta-amyloid levels increased by almost 120% by day 3, and mice developed functional deficits. Bace1 (604252)-null mice showed better outcome after TBI than did wildtype mice. In addition, oral treatment of wildtype mice with a gamma-secretase inhibitor also resulted in decreased amyloid deposition and better outcome after TBI. The findings suggested that the APP secretases have a detrimental role in the initiation of secondary injury after traumatic brain injury.
Heneka et al. (2013) found that Nlrp3-null (606416) or Casp1-null (147678) mice carrying mutations associated with familial Alzheimer disease were largely protected from loss of spatial memory and other sequelae associated with Alzheimer disease, and demonstrated reduced brain caspase-1 and interleukin-1-beta (147720) activation as well as enhanced amyloid-beta clearance. Furthermore, NLRP3 inflammasome deficiency skewed microglial cells to an M2 phenotype and resulted in the decreased deposition of amyloid-beta in the APP/PS1 (104311) model of Alzheimer disease. Heneka et al. (2013) concluded that their results showed an important role for the NLRP3/caspase-1 axis in the pathogenesis of Alzheimer disease.
Using a cDNA probe for the gene encoding the beta-amyloid protein of Alzheimer disease, Delabar et al. (1987) found that leukocyte DNA from 3 patients with sporadic Alzheimer disease and 2 patients with karyotypically normal Down syndrome contained 3 copies of this gene. Because a small region of chromosome 21 containing the ETS2 gene (164740) was duplicated in patients with AD as well as in karyotypically normal Down syndrome, they suggested that duplication of a subsection of the critical segment of chromosome 21 that is duplicated in Down syndrome might be the genetic defect in AD. However, St. George-Hyslop et al. (1987), Tanzi et al. (1987), Podlisny et al. (1987), Warren et al. (1987) and Murdoch et al. (1988) could demonstrate no evidence of duplication of the APP gene in patients with either familial or sporadic Alzheimer disease.
Jones et al. (1992) identified a single missense mutation in the APP gene in a patient with schizophrenia. However, Mant et al. (1992), Carter et al. (1993), and Coon et al. (1993) presented evidence refuting the association.
Retractions
Nikolaev et al. (2009) reported that APP and death receptor-6 (DR6; 605732) activate a widespread caspase-dependent self-destruction program. However, this article was retracted.
The article by Lesne et al. (2006) regarding memory deficits in middle-aged Tg2576 mice was retracted.
In 2 patients with hereditary cerebral hemorrhage with amyloidosis of the Dutch type (HCHWAD; 605714), Levy et al. (1990) identified a 1852G-C transversion in the APP gene, resulting in a glu693-to-gln (E693Q) substitution. The change is referred to as E22Q in the processed amyloid beta peptide. Affected patients usually presented with cerebral lobar hemorrhages before 50 years of age due to the severe cerebral arterial amyloidosis. However, in these patients, parenchymal amyloid deposits were rare, and neurofibrillary tangles were consistently absent, features that clearly distinguished the Dutch phenotype from those related to the 'Flemish' (A692G; 104760.0005) and 'Arctic' (E693G; 104760.0013) mutations (Miravalle et al., 2000).
Bakker et al. (1991) described the use of an E693Q mutation-specific oligonucleotide in the diagnosis of Dutch hereditary cerebral hemorrhage with amyloidosis.
De Jonghe et al. (1998) showed that the E693Q mutation did not result in increased secretion of fibrillogenic beta-amyloid-40 or beta-amyloid-42, consistent with the lack of AD pathology found in patients with this mutation. In contrast, the A692G mutation (104760.0005) upregulated both beta-amyloid-40 and beta-amyloid-42 secretion, consistent with the findings of AD pathology in patients with that mutation. These data corroborated previous findings that increased beta-amyloid secretion, particularly beta-amyloid-42, is specific for AD pathology.
Miravalle et al. (2000) demonstrated in vitro that the E693Q mutation resulted in a high content of beta-sheet amyloid conformation and fast aggregation/fibrillization properties. The E693Q mutant induced cerebral endothelial cell apoptosis, whereas the E693K mutant (104760.0014) did not. The data suggested that different amino acids at codon 693 conferred distinct structural properties to the peptides that appeared to influence the age at onset and aggressiveness of the disease rather than the phenotype.
In affected members of 2 families with early-onset Alzheimer disease-1 (104300), Goate et al. (1991) identified a heterozygous 2149C-T transition in exon 17 of the APP gene, resulting in a val717-to-ile (V717I) substitution. The mutation may have involved a CpG dinucleotide. The substitution created a BclI restriction site which allowed detection of the corresponding change within the PCR product.
Naruse et al. (1991) identified the V717I mutation in 2 unrelated Japanese patients with familial early-onset Alzheimer disease, and Yoshioka et al. (1991) identified it in a third Japanese family.
Failing to find the V717I mutation in 100 patients with early-onset AD, van Duijn et al. (1991) concluded that it accounts for less than 3.6% of all cases with early-onset AD. Schellenberg et al. (1991) did not identify the V717I mutation in 76 families with familial Alzheimer disease, 127 subjects with presumably sporadic Alzheimer disease, 16 patients with Down syndrome, or 256 normal controls.
Karlinsky et al. (1992) reported an AD family from Toronto with the V717I mutation. The family immigrated to Canada from the British Isles in the 18th century. Relationship to one or both of the pedigrees reported by Goate et al. (1991) could not be excluded. In a follow-up report of the family reported by Karlinsky et al. (1992), St. George-Hyslop et al. (1994) noted that 1 family member with the V717I mutation remained clinically healthy with no sign of disease on neurologic or neuropsychologic tests or on brain imaging. The authors suggested that this might be due to the fact that this individual lacked the E4 allele at the APOE locus (107741), his genotype being E2/E3. All 3 living clinically affected family members with the V717I mutation were considerably younger and had the E3/E4 genotype. St. George-Hyslop et al. (1994) suggested that there is an interaction between the development of Alzheimer disease due to mutations in the APP gene and the E4 allele. In contrast, they observed no relationship between the APOE genotype and age of onset or other clinical features in affected members of a large pedigree in which familial AD was linked to chromosome 14 (AD3; 607822).
Maruyama et al. (1996) explored the significance of the fact that 3 mutations in the val717 residue of APP (V717I; V717F; 104760.0003, and V717G; 104760.0004) had been found in patients with familial Alzheimer disease and that these mutations resulted in increased secretion of A-beta-42(43). Functional expression studies showed that the FAD-linked mutations at residue 717 increased the levels or ratios of A-beta-42(43), whereas the secretion of A-beta-40 was decreased. Mutations at residue 717 irrelevant to FAD, except V717K, had little effect on the ratio of beta-42(43). V717K decreased the secretion of beta-42. Overall, the results suggested a specific role of the val717 residue in APP processing and gamma-cleavage.
In affected members of a large Indiana kindred with autopsy-proven Alzheimer disease (104300), Murrell et al. (1991) identified a G-to-T transversion in the APP gene, resulting in a val717-to-phe (V717F) substitution. The substitution is 2 residues beyond the carboxyl terminus of the beta-amyloid peptide subunit isolated from amyloid fibrils. See also V717I (104760.0002) and V717G (104760.0004). Zeldenrust et al. (1993) identified the V717F substitution in 9 of 34 at-risk members of the original Indiana kindred reported by Murrell et al. (1991).
Games et al. (1995) found that brains of transgenic mice overexpressing the V717F mutant protein showed typical pathologic findings of AD, including numerous extracellular thioflavine S-positive A-beta deposits, neuritic plaques, synaptic loss, astrocytosis, and microgliosis.
Bales et al. (1999) quantified the amount of amyloid beta-peptide immunoreactivity as well as amyloid deposits in a large cohort of transgenic mice overexpressing the V717F human APP mutation, with zero, 1, or 2 mouse ApoE (107741) alleles at various ages. Remarkably, no amyloid deposits were found in any brain region of V717F heterozygous mice that were ApoE -/- as old as 22 months of age, whereas age-matched V717F heterozygous animals which were either ApoE +/- or ApoE +/+ displayed abundant amyloid deposition. The amount of A-beta immunoreactivity in the hippocampus was also markedly reduced in an ApoE gene dose-dependent manner, and no A-beta immunoreactivity was detected in the cerebral cortex of V717F heterozygous mice that were ApoE -/- at any of the time points examined. Because the absence of ApoE altered neither the transcription nor the translation of the APP(V717F) transgene nor its processing to A-beta peptide(s), Bales et al. (1999) postulated that ApoE promotes both the deposition and fibrillization of A-beta, ultimately affecting clearance of protease-resistant A-beta/ApoE aggregates. ApoE appears to play an essential role in amyloid deposition in brain, one of the neuropathologic hallmarks of Alzheimer disease.
DeMattos et al. (2004) generated transgenic mice with the V717F mutation that were also null for ApoE, ApoJ (185430), or null for both Apo genes. The double Apo-knockout mice showed early-onset beta-amyloid deposition beginning at 6 months of age and a marked increase in amyloid deposition compared to the other mice. The amyloid plaques were compact and diffuse, were thioflavine S-positive indicating true fibrillar amyloid, and were distributed throughout the hippocampus and some parts of the cortex, contributing to neuritic plaques. The findings suggested that ApoE and ApoJ are not required for amyloid fibril formation. The double Apo knockout mice also had increased levels of intracellular soluble beta-amyloid compared to the other mice. Insoluble beta-42 was similar to the ApoE-null mice, suggesting that ApoE has a selective effect on beta-42. As APP is produced and secreted by neurons in the CNS, and apoE and apoJ are produced and secreted primarily by astrocytes in the CNS, the interaction between the apolipoproteins and beta-amyloid must occur in the interstitial fluid of the brain, an extracellular compartment that is continuous with the CSF. DeMattos et al. (2004) found that ApoE-null and ApoE/ApoJ-null mice had increased levels of beta-amyloid in the CSF and interstitial space, suggesting that ApoE, and perhaps ApoJ, play a role in regulating extracellular CNS beta-amyloid clearance independent of beta-amyloid synthesis. The data suggested that, in the mouse, ApoE and ApoJ cooperatively suppress beta-amyloid deposition.
In affected members of a family with early-onset Alzheimer disease (104300), Chartier-Harlin et al. (1991) identified a 2150T-G transversion in exon 17 of the APP gene, resulting in a val717-to-glu (V717G) substitution. Average age at onset was 59 years. It was the third mutation identified in codon 717 of the APP gene in families with Alzheimer disease (see V717I, 104760.0002 and V717F, 104760.0003).
In affected members of a 4-generation Dutch family with early-onset Alzheimer disease (104300) and hereditary amyloidosis, Hendriks et al. (1992) identified a C-to-G transversion in the APP gene, resulting in an ala692-to-gly (A692G) substitution, which corresponds to A21G in the beta-amyloid protein.
Cras et al. (1998) described the postmortem examination of 2 demented patients with the A692G mutation. The autopsy findings supported the diagnosis of Alzheimer disease in both patients. The neuropathologic abnormalities were remarkable for the large amyloid core senile plaques, the presence of neurofibrillary tangles, and extensive amyloid angiopathy. Leptomeningeal and parenchymal vessels showed extensive deposition of A-beta-amyloid protein. The morphology of the senile plaques was clearly distinct from that described in sporadic AD, in chromosome 14-linked AD patients (AD3; 607822), in AD patients with the APP V717I mutation (104760.0002), and in patients with the APP E693Q mutation (104760.0001) causing the Dutch form of cerebroarterial amyloidosis (605714).
De Jonghe et al. (1998) provided evidence that the A692G mutation resulted in increased secretion of fibrillogenic beta-amyloid-40 and beta-amyloid-42, consistent with the findings of AD pathology in patients with this mutation. These data corroborated the previous findings that increased beta-amyloid secretion, particularly beta-amyloid-42, is specific for AD pathology.
By in vitro functional studies, Walsh et al. (2001) found that the A692G substitution, which they referred to as the 'Flemish variant,' increased the solubility of processed beta-amyloid peptides and increased the stability of peptide oligomers. They concluded that conformational changes in the peptide induced by this mutation would facilitate peptide adherence to the vascular endothelium, creating nidi for amyloid growth. Increased peptide solubility and assembly stability would favor formation of larger amyloid deposits and inhibit their elimination.
In 2 out of 12 AD patients, in 1 out of 60 non-AD patients, and in 1 out of 30 healthy persons, Balbin et al. (1992) identified a 2124C-T transition in exon 17 of the APP gene, resulting in a silent substitution at the protein level. The authors suggested that the variant could be used as a marker for linkage studies involving the APP gene.
In affected members of 2 large Swedish families with early-onset familial Alzheimer disease (104300), Mullan et al. (1992) identified a double mutation in exon 16 of the APP gene: a G-to-T transversion, resulting in lys670-to-asn (K670N) substitution, and an A-to-C transversion, resulting in a met671-to-leu (M671L) substitution. Mullan et al. (1992) suggested that this mutation, which occurs at the amino terminal of beta-amyloid, may be pathogenic because it occurs at or close to the endosomal/lysosomal cleavage site of the molecule. The mean age at onset was 55 years. The 2 families were found to be linked by genealogy. Citron et al. (1992) reported that cultured cells that express an APP cDNA bearing this double mutation produced 6 to 8 times more amyloid beta-protein than cells expressing the normal APP gene. They showed that the met596-to-leu mutation was principally responsible for the increase. (MET596LEU in the APP695 transcript is the equivalent of MET671LEU in the APP770 transcript, which was the basis of the numbering system used by Mullan et al. (1992).) These findings established a direct link between genotype and phenotype.
Felsenstein et al. (1994) found that a neuroglioma cell line expressing the Swedish FAD double mutation showed a consistent 5- to 7-fold increase in the level of the 11-kD potentially amyloidogenic C-terminal fragment. The increase appeared to result from altered cleavage specificity in the secretory pathway from the nonamyloidogenic alpha-secretase site at lys16 to an alternative site at or near the N terminus of the beta protein.
Citron et al. (1994) found that fibroblasts isolated from the Swedish family with the double APP mutation, continuously secreted a homogeneous population of beta-amyloid molecules starting at asp-1 (D672 of beta-APP). There was a consistent and significant elevation of approximately 3-fold of beta-amyloid release from all biopsied skin fibroblasts bearing the FAD mutation. The elevated beta-amyloid levels were found in cells from both patients with clinical Alzheimer disease and presymptomatic subjects, indicating that it is not a secondary event and may play a causal role in the development of the disease. Haass et al. (1995) showed that the increased production of amyloid beta peptide associated with the 'Swedish mutation' resulted from a cellular mechanism which differs substantially from that responsible for the production of amyloid beta peptide from the wildtype gene. In the latter case, A-beta generation requires reinternalization and recycling of the precursor protein. In the Swedish mutation, the N-terminal beta-secretase cleavage of A-beta occurred in Golgi-derived vesicles, most likely within secretory vesicles. Therefore, this cleavage occurred in the same compartment as the alpha-secretase cleavage, which normally prevents A-beta production, explaining the increased A-beta generation by a competition between alpha- and beta-secretase.
Sturchler-Pierrat et al. (1997) observed pathologic features reminiscent of AD in 2 lines of transgenic mice expressing human APP mutations. A 2-fold overexpression of human APP with the Swedish double mutation at positions 670 to 671 combined with the V717I mutation (104760.0002) caused amyloid beta deposition in neocortex and hippocampus of 18-month-old transgenic mice. The deposits were mostly of the diffuse type; however, some congophilic plaques could be detected. In mice with 7-fold overexpression of human APP harboring the Swedish mutation alone, typical plaques appeared at 6 months, which increased with age and were Congo Red-positive at first detection. These congophilic plaques were accompanied by neuritic changes and dystrophic cholinergic fibers. Furthermore, inflammatory processes indicated by a massive glial reaction were apparent. Most notably, the plaques were immunoreactive for hyperphosphorylated tau (MAPT; 157140), reminiscent of early tau pathology. These findings supported a central role of beta-amyloid in the pathogenesis of AD.
Calhoun et al. (1998) studied the pattern of neuron loss in transgenic mice expressing mutant human APP with the 'Swedish mutation.' These mice develop APP-immunoreactive plaques, primarily in neocortex and hippocampus, progressively with age (Sturchler-Pierrat et al., 1997). Calhoun et al. (1998) showed that formation of amyloid plaques led to region-specific loss of neurons in the transgenic mouse. Neuron loss was observed primarily in the vicinity of plaques, but intraneuronal amyloidogenic APP processing could not be excluded as an additional cause. The extent of the observed loss was less than that reported in end-stage AD, possibly because overexpression of APP in the transgenic mouse had a neuroprotective effect.
Hsiao et al. (1996) found that transgenic mice overexpressing the Swedish double mutation had normal learning and memory in spatial reference and alternation tasks at 3 months of age, but showed impairment by 9 to 10 months of age. Brains of the older mice showed a 5-fold increase in the concentration of beta-amyloid derivatives and classic senile plaques with dense amyloid cores.
In 1 of 130 early-onset AD (104300) patients from hospitals throughout France, Carter et al. (1992) identified 2 mutations in the APP gene: a G-to-A transition, resulting in an ala713-to-thr (A713T) substitution, and a G-to-A transition, resulting in a silent change at codon 715. The 713 mutation changes residue 42 of the beta-amyloid protein, considered to be the penultimate or terminal amino acid of this molecule, and thus could potentially alter both endosomal/lysosomal cleavage and the C-terminal sequence of the resulting beta-peptide. The double mutation was present also in 4 healthy sibs and a paternal aunt who was also healthy at age 88. This experience may represent reduced penetrance; additional environmental factors may be necessary for expression of the disorder or an independent genetic factor absent in the affected sib may suppress amyloid formation in the unaffected members of the kindred.
Rossi et al. (2004) reported a family in which at least 6 members spanning 3 generations had Alzheimer disease and strokes associated with a heterozygous A713T mutation. Neuropathologic examination showed neurofibrillary tangles and A-beta-40 and 42-immunoreactive deposits in the neuropil. The vessel walls showed only A-beta-40 deposits, consistent with amyloid angiopathy. There were also multiple white matter infarcts along the long penetrating arteries. Rossi et al. (2004) noted that the A713T mutation lies within the beta-amyloid sequence and adjacent to the gamma-secretase cleavage site.
Peacock et al. (1994) used reverse transcription-polymerase chain reaction, denaturing gradient gel electrophoresis, and direct DNA sequencing to analyze APP exons 16 and 17 from patients with histologically confirmed Alzheimer disease (104300). One patient, who died at age 92, was found to have a 2119C-G transversion, resulting in a glu665-to-asp (E665D) substitution. A sister had died with dementia between 80 and 85 years of age. The same mutation was present in a nondemented relative older than 65 years. Thus, although the mutation was not found in 40 control subjects and 127 dementia patients, its relationship to Alzheimer disease was uncertain. Hitherto, no evidence had been forthcoming that APP mutations are involved in late-onset or sporadic Alzheimer disease.
In affected members of a family with early-onset AD (104300), Eckman et al. (1997) identified a mutation in the APP gene, resulting in an ile716-to-val (I716V) substitution. The mean age at onset was approximately 53 years. Cells transfected with cDNAs bearing the I716V mutation produced more of A-beta-42(43) protein than those transfected with wildtype APP.
In affected members of a family with early-onset AD (104300), Ancolio et al. (1999) identified a mutation in the APP gene, resulting in a val715-to-met (V715M) substitution. Overexpression of V715M in human HEK293 cells and murine neurons reduced total A-beta production and increased the recovery of the physiologically secreted product, APP-alpha. The V715M mutation significantly reduced A-beta-40 secretion without affecting A-beta-42 production in HEK293 cells. However, a marked increase in N-terminally truncated A-beta ending at position 42 was observed, whereas its counterpart ending at position 40 was not affected. These results suggested that, in some cases, familial AD may be associated with a reduction in the overall production of A-beta, but may be caused by increased production of truncated forms of A-beta ending at position 42. This family with the V715M mutation was also reported by Campion et al. (1999), the same family having been ascertained through a population-based survey of early-onset Alzheimer disease.
In a patient with early-onset familial Alzheimer disease (104300), Kamino et al. (1992) identified an A-to-G transition in the APP gene, resulting in a glu693-to-gly (E693G) substitution. The mutation is referred to as E22G in the processed beta-amyloid protein. The proband was from a family with early-onset familial Alzheimer disease spanning 3 generations. He had onset of disease at age 56 years, and postmortem examination found neuritic amyloid plaques and tau-positive neurofibrillary tangles. Moderate to severe amyloid was deposited in the cortical and leptomeningeal arteries. The mutation was not identified in 126 other FAD families. Other mutations of codon 693 cause hereditary cerebral hemorrhage and amyloidosis (see 609095) of the Dutch type (E693Q; 104760.0001) and Italian type (E693K; 104760.0014).
Miravalle et al. (2000) referred to the E693G mutation as the 'Arctic mutation.'
Nilsberth et al. (2001) identified the E693G mutation in affected members of a large Swedish family with AD. Mutation carriers had decreased levels of plasma beta-amyloid-40 and -42. Cells transfected with the mutation showed increased rates and amounts of protofibril formation. Nilsberth et al. (2001) postulated that the pathogenic mechanism for AD in patients with the E693G mutation may involve rapid beta-amyloid protofibril formation leading to accelerated buildup of insoluble beta-amyloid intra- and/or extracellularly.
In vitro, the Arctic mutant form of A-beta forms protofibrils and fibrils at higher rates and in larger quantities than wildtype A-beta. In transgenic mice that expressed the Arctic mutant in neurons, Cheng et al. (2004) found that amyloid plaques formed faster and were more extensive compared to control mice. Cheng et al. (2004) concluded that the Arctic mutation is highly amyloidogenic in vivo.
Basun et al. (2008) restudied the clinical features of the American and Swedish families with the E693G mutation reported by Kamino et al. (1992) and Nilsberth et al. (2001), respectively. They noted that the American family was descended from Swedish immigrants. Affected individuals typically presented between age 52 and 65 years, with slow deterioration of cognitive function typical of AD, as well as some additional symptoms such as disorientation, dysphasia, and dyspraxia. None of the patients had a history of cerebrovascular events. Neuropathologic examination of 2 patients showed severe congophilic angiopathy of multiple vessels, amyloid plaques in a ring form without a core, neurofibrillary tangles, and neuronal loss. The amyloid plaques were strongly immunopositive for beta-amyloid-40 and -42, showed neuritic features, and were negative for Congo red.
Miravalle et al. (2000) reported that a glu693-to-lys (E693K) mutation had been identified in affected members of 3 Italian families with cerebroarterial amyloidosis (605714). The mutation is referred to as E22K in the processed beta-amyloid peptide. The patients presented between 60 and 70 years of age, which was significantly later than those with the Dutch type of cerebral amyloidosis and hemorrhage who have a mutation in the same codon (E693Q; 104760.0001). Neuropathologic examination of 1 Italian patient who had onset at age 45 years revealed extensive beta-amyloid deposits in leptomeningeal and cortical vessels and, to a lesser extent, amyloid plaques in the neuropil of the cerebral cortex. Vascular deposits were primarily labeled by anti-A40 antibody, whereas parenchymal deposits were predominantly revealed by anti-A42 antibody, as in AD. However, neurofibrillary changes were very mild and restricted to the archicortex.
Miravalle et al. (2000) demonstrated in vitro that the E693Q mutation resulted in a high content of beta-sheet amyloid conformation and fast aggregation/fibrillization properties. The E693Q mutant induced cerebral endothelial cell apoptosis, whereas the E693K mutant did not. The data suggested that different amino acids at codon 693 confer distinct structural properties to the peptides that appeared to influence the age at onset and aggressiveness of the disease rather than the phenotype.
Bugiani et al. (2010) reported 4 unrelated Italian families with autosomal dominant hereditary cerebral hemorrhage with amyloidosis caused by the heterozygous E693K mutation. Affected individuals presented with recurrent headache and multiple hemorrhagic strokes between age 44 and 63, followed by epilepsy and cognitive decline in most of them. Several affected individuals became comatose or bedridden, and some died as a result of cerebral hemorrhage. Neuroimaging demonstrated small to large hematomas, subarachnoid bleeding, scars with hemosiderin deposits, multi-infarct encephalopathy, and leukoaraiosis. Multiple brain regions were involved, including both gray and white matter. Postmortem examination of 1 patient showed many small vessels with thickened and/or split walls due to a hyaline congophilic material that was immunoreactive for beta-amyloid-40. Most of the abnormal vessels were in the leptomeninges, in the cerebral and cerebellar cortex, and in the white matter close to the cortex. Beta-amyloid-40 was also detectable in cortical capillaries, and beta-amyloid-42 was found in neuropil of the gray structures. Neurofibrillary tangles and neuritic plaques were not present. The progression of the clinical phenotype correlated with that pathologic findings.
Kumar-Singh et al. (2000) described an aggressive form of Alzheimer disease (104300) caused by a 2208C-T transition in exon 17 of the APP gene, resulting in a thr714-to-ile (T714I) substitution. The mutation directly involved gamma-secretase cleavages of APP, resulting in alteration of the A-beta-42/A-beta-40 ratio 11-fold in vitro. The findings coincided with brain deposition of abundant, predominantly nonfibrillar preamyloid plaques composed primarily of N-truncated A-beta-42 in the absence of A-beta-40. The authors hypothesized that diffuse nonfibrillar plaques of N-truncated A-beta-42 have an essential role in AD pathology.
Edwards-Lee et al. (2005) reported an African American family in which multiple members spanning 3 generations had early-onset AD. Two sibs who were tested were heterozygous for the T714I mutation (104760.0015). The distinctive clinical features in this family were a rapidly progressive dementia starting in the fourth decade, seizures, myoclonus, parkinsonism, and spasticity. Variable features included aggressiveness, visual disturbances, and pathologic laughter.
In 2 brothers from Iowa with autosomal dominant cerebroarterial amyloidosis (605714), Grabowski et al. (2001) identified a mutation in the APP gene, resulting in an asp694-to-asn (D694N) substitution. This corresponds to residue N23D of the beta-amyloid peptide. Neither brother had symptomatic hemorrhagic stroke. Neuropathologic examination of the proband revealed severe cerebral amyloid angiopathy, widespread neurofibrillary tangles, and unusually extensive distribution of beta-amyloid-40 in plaques.
Greenberg et al. (2003) identified the D694N mutation in 2 affected members of a Spanish family with autosomal dominant dementia, occipital calcifications, leukoencephalopathy, and hemorrhagic strokes (see 605714).
Pasalar et al. (2002) reported an Iranian family with 9 individuals in 3 generations affected by Alzheimer disease (104300) with an average age of onset of 55 years. Two patients who were genotyped had a 2207A-G mutation in exon 17 of the APP gene, resulting in a thr714-to-ala (T714A) substitution. Pasalar et al. (2002) noted that this mutation is one of several reported in the cluster between codons 714 and 717 (1 helical turn) just outside the C terminus of the beta-amyloid sequence, and is likely to disrupt APP processing such that more beta-amyloid-42 would be produced.
In 4 affected members of an Italian family with autosomal dominant cerebral amyloid angiopathy (605714), Obici et al. (2005) identified a G-to-C transversion in the APP gene, resulting in a leu705-to-val (L705V) substitution, corresponding to residue 34 of the beta-amyloid protein. The mutation was not identified in 100 controls. Clinically, the patients had multiple intracerebral hemorrhages, but only 1 affected family member had cognitive impairment. Neuropathologic analysis of 2 patients showed severe selective cerebral arterial amyloidosis in leptomeningeal and cortical vessel walls without parenchymal amyloid plaques or neurofibrillary tangles. Revesz et al. (2009) referred to the L705V change as the Piedmont variant.
In a cohort of 65 families with autosomal dominant early-onset Alzheimer disease (ADEOAD), 5 had severe associated cerebral amyloid angiopathy (see 104300 and 605714). Rovelet-Lecrux et al. (2006) found duplication of the APP locus in these 5 index cases. In the corresponding families, the duplication was found only in affected members and not in healthy subjects over 60 years of age.
Guyant-Marechal et al. (2008) reported a family in which 3 individuals with a 0.55-Mb duplication of the APP locus showed highly variable phenotypes. The proband developed bradykinesia, memory problems, and apraxia at age 44. She later had paranoid delusions with visual hallucinations associated with bilateral tremor and rigidity, and died at age 55. Neuropathologic examination showed cerebral amyloid angiopathy, amyloid plaques, neurofibrillary tangles, and numerous Lewy bodies. A second mutation carrier had had partial visual seizures at age 52 associated with white matter changes and multiple microbleeds on MRI. Cognitive assessment was normal 1 year later. The third mutation carrier developed memory complaints at age 52 and showed mild cognitive decline 5 years later. MRI showed a left frontal intracranial hemorrhage.
In 2 sibs with early-onset AD (104300), Murrell et al. (2000) identified a heterozygous G-to-C transversion in exon 17 of the APP gene, resulting in a val717-to-leu (V717L) substitution. Age at onset was in the late thirties. Other mutations at residue 717 include V717I (104760.0002), V717F (104760.0003), and V717G (104760.0004).
Godbolt et al. (2006) identified the V717L substitution in affected members of a second family with AD. Two patients reported hallucinations. Age at onset ranged from 48 to 57, later than that in the family reported by Murrell et al. (2000).
In a patient with early-onset progressive Alzheimer disease (104300), Di Fede et al. (2009) identified a homozygous C-to-T transition in exon 16 of the APP gene resulting in an ala673-to-val substitution (A673V), corresponding to position 2 of amyloid beta. The mutation was also found in homozygosity in the proband's younger sister, who had multiple domain mild cognitive impairment (MCI), believed to a high risk condition for the development of clinically probable Alzheimer disease (Petersen et al., 2001). The proband developed progressive dementia at age 36 and was noncommunicative and could not walk by age 44. Serial MRI showed progressive cortico-subcortical atrophy. Cerebrospinal fluid analysis showed decreased A-beta-1-42 and increased total and 181T-phosphorylated tau compared to controls and similar to subjects with Alzheimer disease. In the plasma of both the patient and his homozygous sister, amyloid-beta-1-40 and amyloid-beta-1-42 were higher than in nondemented controls, whereas the A673V heterozygous carriers from the family that were tested had intermediate amounts. None of 6 heterozygous individuals in the family had any evidence of dementia when tested at ages ranging from 21 to 88. The A673V mutation affected APP processing, resulting in enhanced beta-amyloid production and formation of amyloid fibrils in vitro. Coincubation of mutated and wildtype peptides conferred instability on amyloid beta aggregates and inhibited amyloidogenesis and neurotoxicity. Di Fede et al. (2009) concluded that the interaction between mutant and wildtype amyloid beta, favored by the A-to-V substitution at position 2, interferes with nucleation or nucleation-dependent polymerization or both, hindering amyloidogenesis and neurotoxicity and thus protecting the heterozygous carriers.
Using whole-genome sequence data from 1,795 Icelanders, Jonsson et al. (2012) identified a coding SNP in the APP gene, rs63750847 (A673T). This SNP was significantly more common in a control group of individuals aged 85 years or older without a diagnosis of Alzheimer disease (104300) than in a group of Alzheimer disease patients (0.62% vs 0.13%, respectively; OR = 5.29; p = 4.78 x 10(-7)). The SNP was enriched among a group of controls who were cognitively intact at age 85 years (0.79%; OR = 7.52; p = 6.92 x 10(-6)). Among 3,673 noncarriers and 41 carriers of the A673T variant, all without a diagnosis of Alzheimer disease, Jonsson et al. (2012) found on average a 1.03-unit difference across the 80 to 100 age range on a test of cognitive performance (average 6.49 and 6.39 determinations per individual, respectively), with the carriers having a score indicative of better conserved cognition. By Western blot analysis of cell supernatants, Jonsson et al. (2012) found that the A673T variant results in reduced production of extracellular APP fragments generated by processing at the beta site with a slight increase in fragments produced using the alpha site. This observation was confirmed by immunoassay. Jonsson et al. (2012) also found that the production of amyloidogenic peptides A-beta-40 and A-beta-42 was approximately 40% less by the A673T variant than by wildtype APP. In contrast to A673T, the A673V substitution (104760.0022) resulted in markedly increased APP processing at the beta site, decreased processing at the alpha site, and greatly enhanced A-beta-40 and A-beta-42 production. These results were consistent with a protective effect of the A673T variant and illustrated clearly that position 673 of APP is capable of regulating proteolytic processing by BACE1 (604252).
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