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Review
. 2022 Aug;17(8):1666-1674.
doi: 10.4103/1673-5374.332127.

Amyloid-beta peptide and tau protein crosstalk in Alzheimer's disease

Alejandro R Roda  1 , Gabriel Serra-Mir  1 , Laia Montoliu-Gaya  2 , Lidia Tiessler  1 , Sandra Villegas  1
Affiliations
Review

Amyloid-beta peptide and tau protein crosstalk in Alzheimer's disease

Alejandro R Roda et al. Neural Regen Res. 2022 Aug.

Abstract

Alzheimer's disease is a neurodegenerative disease that accounts for most of the 50-million dementia cases worldwide in 2018. A large amount of evidence supports the amyloid cascade hypothesis, which states that amyloid-beta accumulation triggers tau hyperphosphorylation and aggregation in form of neurofibrillary tangles, and these aggregates lead to inflammation, synaptic impairment, neuronal loss, and thus to cognitive decline and behavioral abnormalities. The poor correlation found between cognitive decline and amyloid plaques, have led the scientific community to question whether amyloid-beta accumulation is actually triggering neurodegeneration in Alzheimer's disease. The occurrence of tau neurofibrillary tangles better correlates to neuronal loss and clinical symptoms and, although amyloid-beta may initiate the cascade of events, tau impairment is likely the effector molecule of neurodegeneration. Recently, it has been shown that amyloid-beta and tau cooperatively work to impair transcription of genes involved in synaptic function and, more importantly, that downregulation of tau partially reverses transcriptional perturbations. Despite mounting evidence points to an interplay between amyloid-beta and tau, some factors could independently affect both pathologies. Thus, the dual pathway hypothesis, which states that there are common upstream triggers causing both amyloid-beta and tau abnormalities has been proposed. Among others, the immune system seems to be strongly involved in amyloid-beta and tau pathologies. Other factors, as the apolipoprotein E ε4 isoform has been suggested to act as a link between amyloid-beta and tau hyperphosphorylation. Interestingly, amyloid-beta-immunotherapy reduces not only amyloid-beta but also tau levels in animal models and in clinical trials. Likewise, it has been shown that tau-immunotherapy also reduces amyloid-beta levels. Thus, even though amyloid-beta immunotherapy is more advanced than tau-immunotherapy, combined amyloid-beta and tau-directed therapies at early stages of the disease have recently been proposed as a strategy to stop the progression of Alzheimer's disease.

Keywords: Alzheimer; aggregation; amyloid-beta; dementia; immunotherapy; inflammation; neurodegeneration; tau.

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Conflict of interest statement

Conflicts of interest: The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Amyloid precursor protein (APP) processing. (A) α- and γ-secretase act in the non-amyloidogenic pathway, whereas the activity of β-secretase (or BACE) instead of α-secretase defines the amyloidogenic pathway generating the Aβ peptide. BACE1 hydrolyses the β-site (M671-D672 bond) and BACE2 cleaves the β’-site (681Y-682E bond), rendering an N-t truncated form of the precursor (E11-Xx), although also cleaves the β-site. Thus, β′-site cleavage is amyloidolytic rather than amyloidogenic. Finally, γ-secretase releases the Aβ peptide, or its N-t truncated form, after preferentially cleaving the V711-D712 and A713-T714 bonds rendering Aβ1–40 and Aβ1–42, respectively. (B) Target proteolytic sites in the Aβ peptide. (C) Some of the main FAD-related mutations in human APP. ACID: APP intracellular domain; Aβ: amyloid-beta peptide; BACE: beta-site APP cleaving enzyme; CTF: carboxyterminal fragments; FAD: familial Alzheimer’s disease.
Figure 2
Figure 2
The amyloid cascade hypothesis (ACH). Whether by an increase in production (FAD) or an impairment in clearance (SAD), Aβ peptide accumulates through an aggregation pathway populated by different species, i.e. monomers, oligomers, fibrils, and amyloid plaques. Aβ oligomers are the most toxic species, and to a lesser extent fibrils, causing calcium disruption, mitochondrial failure, inflammatory response, oxidative stress, transcriptional impairment, synaptic loss and, finally, neuronal death. In addition, Aβ oligomers induce the hyperphosphorylation of tau, which aggregates into oligomers that evolve to paired helical filaments and finally to NFTs. Tau oligomers are also toxic for neurons, with a strong effect on synapses, and, in turn, induce the formation of Aβ oligomers. In addition to this positive feedback between Aβ and tau aggregation, Aβ and tau cooperatively work to lead to neuronal death. Although still controversial, the ACH covers the multifactorial nature of AD. Aβ: Amyloid-beta peptide; FAD: familial Alzheimer’s disease; NFTs: neurofilament tangles; PHF: paired helical filaments; SAD: sporadic Alzheimer’s disease.
Figure 3
Figure 3
Amyloid fibril formation and three-dimensional structure. (A) Aggregation of Aβ from the formation of different kind of oligomers to amyloid fibrils. (B) Aβ1–40 amyloid fibrils are composed by multiple ordered trimers. The N-termini are completely solvent-exposed, whereas the C-termini are buried in the hydrophobic core (PDB 2M4J) (Lu et al., 2013). Each color represents a monomer. (C) Aβ1–42 amyloid fibrils are made of dimers. The N-termini are slightly solvent-exposed, whereas the C-termini are completely buried in the interface between monomers (PDB 5OQV) (Gremer et al., 2017). Each monomer in the dimer shows higher β-content than in the trimer. Each color represents a monomer. Images were generated with the Swiss-PdbViewer software (Guex and Peitsch, 1997). Aβ: Amyloid-beta peptide; PDB: protein data bank.
Figure 4
Figure 4
Three-dimensional structure of tau NFTs and tau isoforms scheme. (A) Six different isoforms of tau are expressed in the adult human central nervous system via alternative splicing of the MAPT gene. Regulated expression of exons 2 and 3 gives rise to tau isoforms with 0, 1, or 2 N-terminal inserts whereas exclusion or inclusion of exon 10 leads to expression of tau isoforms with three (3R) or four (4R) microtubule-binding repeats. (B) Paired helical filaments from AD brain. The structure shows the fuzzy core formed by aggregated repeats (residues G304-E380) (PDB 6HRE) (Falcon et al., 2018). Each color represents a monomer. Images were generated with the Swiss-PdbViewer software (Guex and Peitsch, 1997). AD: Alzheimer’s disease; MAPT: microtubule associated protein tau; PDB: protein data bank.
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