Alzheimer’s Disease “Non-amyloidogenic” p3 Peptide Revisited: A Case for Amyloid-α

Abstract

Amyloid-β (Aβ) is an intrinsically disordered peptide thought to play an important role in Alzheimer's disease (AD). It has been the target of most AD therapeutic efforts, which have repeatedly failed in clinical trials. A more predominant peptidic fragment, formed through alternative processing of the amyloid precursor protein, is the p3 peptide. p3 has received little attention, which is possibly due to the prevailing view in the AD field that it is "non-amyloidogenic." By probing the self-assembly of this peptide, we found that p3 aggregates to form oligomers and fibrils and, when compared with Aβ, displays enhanced aggregation rates. Our findings highlight the solubilizing effect of the Nterminus of Aβ and the favorable formation of structures formed through C-terminal hydrophobic peptide interfaces. Based on our findings, we suggest a reevaluation of the current therapeutic approaches targeting only the β-secretase pathway of AD, given that the αsecretase pathway is also amyloidogenic.

A crystal-structural study of Pauling–Corey rippled sheets

“…The (L,L,L)-triphenylalanine (i.e., FFF) and (D,D,D)-triphenylalanine (i.e., fff) peptides were synthesized by standard Fmoc-based, solid-phase peptide chemistry, following our previously reported protocols. 39,51 Both peptides were synthesized using preloaded, Fmocphenylalanine 4-alkoxybenzyl alcohol Wang resin: Fmoc-L-Phe-Wang (Sigma) or Fmoc-D-Phe-Wang (Fisher). All syntheses were performed manually at 0.2 mM scale relative to resin loading.…”

Tipping the Scales: Peptide-Dependent Dysregulation of Neural Circuit Dynamics in Alzheimer’s Disease

“…In turn, CTFα, similarly to CTFβ, undergoes secondary cleavage by γ-secretase, leading to extracellular release of an N-terminal truncated form of Aβ, known as p3. Little is known about the p3 peptide, although recent intriguing work has suggested that it may also possess amyloidogenic properties (Kuhn et al, 2020). CTFη on the other hand, can be further cleaved by α-or β-secretase, resulting in the extracellular release of amyloid-eta-α (Aη-α) or amyloideta-β (Aη-β), respectively (Willem et al, 2015) (see figure).…”

Liquid-Liquid Phase Separation Protects Amyloidogenic and Aggregation-Prone Peptides in Heterologous Expression Systems

“…: (i) two peptides from the highly amyloidogenic regions of the transforming growth factor β-induced (TGFBI) protein associated with corneal dystrophies, [16,17] which were previously shown to be highly insoluble in an E. coli -based expression; [18] and (ii) an engineered variant of Aβ 17-40 peptide (Aβ-P3*) associated with Alzheimer’s disease. [19] Aβ-P3 exhibits faster kinetics of fibril formation than other full-length Aβ peptides, [20] resulting in increased cytotoxicity in cultured neuronal cells. [21] Because it lacks the N-terminus region of other Aβ peptides that helps maintain partial solubility, [22] Aβ-P3 peptide is very unstable, resulting in accelerated aggregation and self-assembly of fibrils almost immediately after production.…”

“…[21] Because it lacks the N-terminus region of other Aβ peptides that helps maintain partial solubility, [22] Aβ-P3 peptide is very unstable, resulting in accelerated aggregation and self-assembly of fibrils almost immediately after production. [20] Using fluorescence imaging, we find that following overexpression the fusion constructs form membraneless organelles in E. coli , subsequently facilitating their purification while at the same time preventing premature aggregation. Once the LLPS-forming tag is cleaved off, the amyloidogenic peptides spontaneously self-assemble into amyloid fibrils amenable to structural studies as shown from TEM observations.…”

“…Fibrils formed by Aβ-P3*peptides (Figure 3c) exhibited a diameter of approximately 20 nm and twists in their ribbon-like features, which is consistent with previously observed TEM images of various types of Aβ fibrils. [20,25]…”