Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2012 Jan;120 Suppl 1(Suppl 1):125-139.
doi: 10.1111/j.1471-4159.2011.07478.x. Epub 2011 Nov 28.

Soluble Aβ oligomer production and toxicity

Megan E Larson  1   2   3 , Sylvain E Lesné  1   2   3
Affiliations
Review

Soluble Aβ oligomer production and toxicity

Megan E Larson et al. J Neurochem. 2012 Jan.

Abstract

For nearly 100 years following the first description of this neurological disorder by Dr Alois Alzheimer, amyloid plaques and neurofibrillary tangles have been hypothesized to cause neuronal loss. With evidence that the extent of insoluble, deposited amyloid poorly correlated with cognitive impairment, research efforts focused on soluble forms of Aβ, also referred as Aβ oligomers. Following a decade of studies, soluble oligomeric forms of Aβ are now believed to induce the deleterious cascade(s) involved in the pathophysiology of Alzheimer's disease. In this review, we will discuss our current understanding about endogenous oligomeric Aβ production, their relative toxicity in vivo and in vitro, and explore the potential future directions needed for the field.

PubMed Disclaimer

Conflict of interest statement

Disclosures: The authors declare no conflict of interests

Figures

Figure 1
Figure 1. Proposed model for endogenous oligomeric Aβ production
Based on our current knowledge, Aβ monomers and trimers are produced and secreted by neurons. Of note, the N-terminus of Aβ is color-coded in blue, the central domain of Aβ in white and the C-terminus of Aβ is shown in red. The assembling of Aβ molecules within oligomers was based on our observations of epitope availability using a large panel of Aβ antibodies (82E1, 6E10, BAM10, 4G8, 40- and 42-end specific Aβ antibodies, A11 and OC). Once in the interstitial fluid, Aβ oligomers follow a trimer-based expansion in size under physiological conditions/normal aging. These species evade fibrillar formation. Upon the presence of an unidentified factor, monomeric Aβ becomes misfolded allowing the peptide to enter the fibrillar oligomer pathway, whose first step corresponds to the formation of Aβ dimers. Dimers can rapidly expand to create dimer-based protofibrils, ultimately contributing to the formation of fibrillar Aβ as amyloid plaques.
Figure 2
Figure 2. Temporal accumulation of endogenous Aβ dimers in brain tissue of Tg2576 mice
(A) Western blots showing the relative levels of Aβ dimers detected following immunoprecipitation using formic acid extracts. Dimeric Aβ levels increase in parallel to plaque accumulation in Tg2576, suggesting that dimers are closely related to deposited amyloid. (B) Densitometry analysis of formic acid-soluble Aβ monomers and dimers in Tg2576. Empty circles represent monomeric Aβ while filled black circles correspond to Aβ dimers (n = 3/group). (C) Relative ratio between Aβ monomers and Aβ dimers in Tg2576.*, non-specific band due to the immunoprecipitation.
Figure 3
Figure 3. Comparison between endogenous Aβ species secreted by mature Tg2576 primary cortical neurons and 7PA2 cells
(A, B) Western blots showing the relative levels of Aβ oligomers detected with 6E10 following immunoprecipitation using 1 mL of conditioned medium. While dimeric Aβ levels is preferentially secreted by 7PA2 cells (B), Aβ trimers are produced and secreted by primary neurons derived from Tg2576 mice (A). The observed profile in neurons (A) suggests a trimer-based oligomerization process under physiological conditions.
Figure 4
Figure 4. Epitope mapping for Aβ*56 in Tg2576 soluble extracts
Immunoprecipitation/Western blots showing the detection profile of Aβ*56 present in Tg2576 mouse brains. A comparison between 6E10, A11 and OC antibodies (kind gifts from Rakez Kayed and Charles Glabe) is presented. The 6E10+/A11+/OC− profile characterizes Aβ*56 as a non-fibrillar Aβ oligomer. * indicate non-specific bands generated by the amplification process.
Figure 5
Figure 5. Relationship between endogenous low molecular weight Aβ oligomers and Aβ*56 in human brain tissue
(A, B) Linear regression analyses between the relative levels of soluble Aβ dimers (A) or trimers (B) and Aβ*56 detected in extracellular-enriched protein fractions of human brain tissue from the Religious Order Study (n = 88). Dimeric Aβ levels showed no association with Aβ*56 whereas the abundance of Aβ trimers was positively correlated with Aβ*56 brain levels. (Rho is indicated next to the P-value for Spearman Rank Correlation. Correlations were performed using the whole cohort, n = 88.)
Figure 6
Figure 6. Proposed model for the expression profile of endogenous Aβ oligomers in human brain tissue
We analyzed human brain tissue from 158 subjects with ages of 1 to 98 years at the time of death. Two cohorts were used for this study (Lesne et al., under review): 49 brain samples were from healthy subjects (from 1 to 62 years) and 89 from subjects with preclinical AD, MCI or AD. Briefly our findings indicate that in healthy subjects Aβ*56 was first detected in the 5th decade of life preceding elevations in Aβ trimers and dimers observed in the 6th and 7th decades. In preclinical AD, Aβ*56 appeared to reach a plateau. In MCI brains, Aβ*56 levels decreased significantly while Aβ trimers levels rose sharply. At this stage, brain levels of Aβ dimers slowly elevated. One possible explanation for this change in the relative expression of these species might be due to a destabilization of the non-fibrillar oligomerization pathway in favor of the fibrillar oligomerization pathway. Finally in AD brain tissue, Aβ dimers were increased while levels of Aβ*56 and Aβ trimers fell to discrete amounts. Such proposed scenario must need to be tested in longitudinal studies.
Figure 7
Figure 7. Correlation between extracellular levels of the oligomeric Aβ assembly, Aβ*56, and disease-relevant tau changes in AD brains
Using a very well cohort of the Religious Order Study, we measured Aβ*56 levels in the extracellular-enriched protein fraction as previously reported (Lesne et al., 2006) as well as soluble total and disease-relevant tau species (using Tau5 and Alz50 antibodies). All protein levels were normalized to the neuron-specific nuclear protein, NeuN, to compensate for neuronal cell death across groups. (A) Representative quantitative western blot for tau5/Alz50 in 30 subjects of our cohort (10 preclinical, 10 MCI and 10 AD) using a Li-Cor Odyssey system. (B) Quantification of soluble Alz50-tau levels revealed disease-relevant tau changes in MCI and AD brains. (C) Linear regression analysis between soluble Alz50-tau and Aβ*56 levels indicated a strong positive correlation in AD brains. Abbreviations: PC, preclinical AD; MCI, mild cognitive impairment; AD, Alzheimer’s disease.
Figure 8
Figure 8. Receptors and signaling pathways potentially modulated by endogenous Aβ oligomers
Among the various receptors proposed to act as oligomeric Aβ receptors, only a handful of postsynaptic receptors appear to be relevant to endogenously produced soluble Aβ entities: PrPc, EphB2, RAGE, α7nAChR, Glutamate transporters, and possibly NMDAR. Since no endogenous Aβ oligomer has been directly shown to bind to NMDARs, and since most signaling pathways altered by naturally produced Aβ oligomers disturb physiological NMDAR transducers or NMDAR expression, Aβ oligomers might act as indirect modulators of NMDAR activity.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Arancio O, Zhang HP, Chen X, et al. RAGE potentiates Abeta-induced perturbation of neuronal function in transgenic mice. Embo J. 2004;23:4096–4105. - PMC - PubMed
    1. Balducci C, Beeg M, Stravalaci M, et al. Synthetic amyloid-beta oligomers impair long-term memory independently of cellular prion protein. Proc Natl Acad Sci U S A. 2010;107:2295–2300. - PMC - PubMed
    1. Barghorn S, Nimmrich V, Striebinger A, et al. Globular amyloid beta-peptide oligomer - a homogenous and stable neuropathological protein in Alzheimer’s disease. J Neurochem. 2005;95:834–847. - PubMed
    1. Barry AE, Klyubin I, Mc Donald JM, Mably AJ, Farrell MA, Scott M, Walsh DM, Rowan MJ. Alzheimer’s Disease Brain-Derived Amyloid-{beta}-Mediated Inhibition of LTP In Vivo Is Prevented by Immunotargeting Cellular Prion Protein. J Neurosci. 2011;31:7259–7263. - PMC - PubMed
    1. Benilova I, De Strooper B. Prion protein in Alzheimer’s pathogenesis: a hot and controversial issue. EMBO Mol Med. 2010;2:289–290. - PMC - PubMed

Publication types

MeSH terms

Substances