Is the p3 Peptide (Aβ17-40, Aβ17-42) Relevant to the Pathology of Alzheimer’s Disease?1

Kuhn, Ariel J.; Raskatov, Jevgenij A.

doi:10.3233/jad-191201

Cited by 20 publications

(33 citation statements)

References 97 publications

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“…that large hydrophobic residue patches frequently associate to form “steric zippers” . A hydrophobic steric zipper is plausible in the case of p3 given that the two amyloidogenic, hydrophobic patches of Aβ (LVFFAE and AIIGLMVGGVV) are also found in p3 (Figure A). To further investigate if fibrillar Aβ and p3 have conformational similarities, the OC antibody, which recognizes conformation-specific epitopes of amyloid fibrils, was employed (Figure F).…”

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confidence: 99%

“…This peptide, termed p3, has received remarkably little attention, and it is largely regarded as benign. However, its biophysical and biological properties remain unclear and inconsistent, as discussed in our recent review and summarized in Table S1. Some have described p3 as neuroprotective, while others have demonstrated that p3 exhibits significant cytotoxicity. , Whereas p3 is often referred to as soluble and “non-amyloidogenic,” − several studies found that p3 formed “amorphous aggregates” and “lattice-like” networks , and, possibly, amyloid fibrils. , One study, conducted by Vandersteen et al, revealed what were described as fibrillar fragments, shorter and dissimilar to those formed by Aβ.…”

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“…Despite the aforementioned studies revealing fibrillar-like morphologies for p3, potentially indicative of amyloidogenicity, the field still recognizes p3 production as an alternative, neuroprotective, and “non-amyloidogenic” pathway of APP processing. ,− To deconvolute these conflicting claims, we sought out to investigate the aggregation propensity of p3. We hypothesized, based on the hydrophobicity and large regions of predicted amyloidogenicity, that p3 could aggregate to form oligomers and fibrils.…”

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“…(A) Fibril structure and sequence of Aβ(1–40), with p3(17–40) indicated in purple. Highlighted regions (17–22 and 30–40) indicate the amyloidogenic regions of Aβ, calculated by AGGRESCAN . TEM images of fibrillar (B) p3 and (C) Aβ.…”

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

Kuhn

Abrams

Knowlton

et al. 2020

ACS Chem. Neurosci.

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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.

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

Kuhn

Abrams

Knowlton

et al. 2020

ACS Chem. Neurosci.

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“…Further supporting the importance of the N-terminus of Aβ are studies of the p3 peptide, an alternative cleavage product to full-length Aβ from the amyloid precursor protein . The p3 peptide, which lacks residues 1–16 has been described as “non-amyloidogenic”, incapable of forming oligomers, devoid of any synaptotoxic effect, and even neuroprotective. − However, a recent review from the Raskatov group has highlighted and summarized inconsistencies within the literature regarding biophysical and biological properties of the p3 peptide and its importance in Alzheimer’s diease. − In a subsequent investigation, the Raskatov group demonstrated that the p3 peptide is capable of assembling to form amyloidogenic fibrils and toxic oligomers . These recent findings suggest that Aβ 1–16 may actually be less important than thought.…”

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Effects of N-Terminal Residues on the Assembly of Constrained β-Hairpin Peptides Derived from Aβ

et al. 2020

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This paper describes the synthesis, solution-phase biophysical studies, and X-ray crystallographic structures of hexamers formed by macrocyclic β-hairpin peptides derived from the central and C-terminal regions of Aβ, which bear “tails” derived from the N-terminus of Aβ. Soluble oligomers of the β-amyloid peptide, Aβ, are thought to be the synaptotoxic species responsible for neurodegeneration in Alzheimer’s disease. Over the last 20 years, evidence has accumulated that implicates the N-terminus of Aβ as a region that may initiate the formation of damaging oligomeric species. We previously studied, in our laboratory, macrocyclic β-hairpin peptides derived from Aβ16–22 and Aβ30–36, capable of forming hexamers that can be observed by X-ray crystallography and SDS-PAGE. To better mimic oligomers of full length Aβ, we use an orthogonal protecting group strategy during the synthesis to append residues from Aβ1–14 to the parent macrocyclic β-hairpin peptide 1, which comprises Aβ16–22 and Aβ30–36. The N-terminally extended peptides N+1, N+2, N+4, N+6, N+8, N+10, N+12, and N+14 assemble to form dimers, trimers, and hexamers in solution-phase studies. X-ray crystallography reveals that peptide N+1 assembles to form a hexamer that is composed of dimers and trimers. These observations are consistent with a model in which the assembly of Aβ oligomers is driven by hydrogen bonding and hydrophobic packing of the residues from the central and C-terminal regions, with the N-terminus of Aβ accommodated by the oligomers as an unstructured tail.

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A robust preparation method for the amyloidogenic and intrinsically disordered amyloid‐α peptide

Kuhn

Raskatov

2022

Journal of Peptide Science

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Recent findings suggest that amyloid-β (Aβ) may not be the only peptidic culprit for the cognitive decline observed in patients with Alzheimer's disease. A C-terminal fragment of Aβ, amyloid-α (Aα), also known as p3, has been shown to form amyloidogenic oligomers and fibrils more rapidly than Aβ. However, the insolubility and aggregation propensity of this 24-26-residue peptide make it exceptionally difficult to produce, purify, and subsequently study. This paper reports a reproducible, multi-step method for the purification and pre-treatment of Aα and related analogues, yielding 95%-99% pure peptides. We anticipate that the methods described herein will permit previously inaccessible biophysical and biological experiments that may be critical to understanding the role of this too long overlooked peptide in AD disease pathology.

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Is the p3 Peptide (Aβ17-40, Aβ17-42) Relevant to the Pathology of Alzheimer’s Disease?1

Cited by 20 publications

References 97 publications

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

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

Effects of N-Terminal Residues on the Assembly of Constrained β-Hairpin Peptides Derived from Aβ

A robust preparation method for the amyloidogenic and intrinsically disordered amyloid‐α peptide

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