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Alzheimer's Disease "Non-amyloidogenic" p3 Peptide Revisited: A Case for Amyloid-?.

ABSTRACT: Amyloid-? (A?) 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 A?, displays enhanced aggregation rates. Our findings highlight the solubilizing effect of the N-terminus of A? 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 ?-secretase pathway of AD, given that the ?- secretase pathway is also amyloidogenic.

SUBMITTER: Kuhn AJ

PROVIDER: S-EPMC7443049 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Alzheimer's Disease "Non-amyloidogenic" p3 Peptide Revisited: A Case for Amyloid-α.

Kuhn Ariel J AJ Abrams Benjamin S BS Knowlton Stella S Raskatov Jevgenij A JA

ACS chemical neuroscience 20200522 11

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-ass ...[more]

PMID: 32412731

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Project description:The cause of Alzheimer's disease (AD) is poorly understood. In 1991, the amyloid hypothesis postulated that ?-amyloid (A?) accumulation is a key element. It follows that clearing the brain of A? would be beneficial, which has not been the case. Therefore, A? is likely a result, not a cause, of AD and may be protective rather than harmful. The apolipoprotein E4 (apoE4) allele is the strongest genetic risk factor for AD. Klotho (KL), encoded by the KL gene, may be another AD-related protein. FGF21 is a circulating endocrine hormone, mainly secreted by the liver, mostly during fasting. FGF21 acts by binding to its receptor FGFR1 and co-receptor ?-klotho. FGF21 is neuroprotective and could delay onset of AD. In the present study, the KL protein structure was examined to determine whether it may interact with A?. Protein data bank (pdb) entries for klotho and A? were searched on the RCSB Protein Data Bank for ?-KL and AD amyloid ?-peptide. The protein structures were superimposed and aligned on PYMOL v2.3.4 with the super command, which super aligns two protein selections. To evaluate the conservation and alignment of the A? and KL genomes across species, BLAT, the Blast-Like Alignment Tool of the UCSC Genome Browser, was used. The amino acid residues phe76-val96 of KL aligned closely with residues asp7-asn27 of A?. Cross-species comparison of KL revealed a high degree of alignment and conservation in the chimp and 27 other primates; however, less alignment and conservation were observed in the mouse, dog and elephant, even less in the chicken, western clawed frog (Xenopus tropicalis), zebrafish and lamprey. The current finding of amino acid residues phe76-val96 of klotho aligning closely with residues asp7-asn27 of A? suggests that A? can enhance the ability of klotho to draw FGF21 to regions of incipient neurodegeneration in AD. The problem arises with age. Older individuals do not heal or repair tissue damage as well as younger individuals. As neurodegeneration advances in an older individual, perhaps caused by neuroinflammation related to herpes simplex virus type 1, increasing amounts of amyloid are produced, forming an adhesive web, as the brain tries to hold the pathologic process in check. Meanwhile, the damage increases and spreads. Progressive neurodegeneration and cognitive decline are the outcome.

Project description:The amyloid cascade hypothesis proposes that excessive accumulation of amyloid beta-peptides is the initiating event in Alzheimer's disease. These neurotoxic peptides are generated from the amyloid precursor protein via sequential cleavage by β- and γ-secretases in the 'amyloidogenic' proteolytic pathway. Alternatively, the amyloid precursor protein can be processed via the 'non-amyloidogenic' pathway which, through the action of the α-secretase a disintegrin and metalloproteinase (ADAM) 10, both precludes amyloid beta-peptide formation and has the additional benefit of generating a neuroprotective soluble amyloid precursor protein fragment, sAPPα. In the current study, we investigated whether the orphan drug, dichloroacetate, could alter amyloid precursor protein proteolysis. In SH-SY5Y neuroblastoma cells, dichloroacetate enhanced sAPPα generation whilst inhibiting β-secretase processing of endogenous amyloid precursor protein and the subsequent generation of amyloid beta-peptides. Over-expression of the amyloid precursor protein partly ablated the effect of dichloroacetate on amyloidogenic and non-amyloidogenic processing whilst over-expression of the β-secretase only ablated the effect on amyloidogenic processing. Similar enhancement of ADAM-mediated amyloid precursor protein processing by dichloroacetate was observed in unrelated cell lines and the effect was not exclusive to the amyloid precursor protein as an ADAM substrate, as indicated by dichloroacetate-enhanced proteolysis of the Notch ligand, Jagged1. Despite altering proteolysis of the amyloid precursor protein, dichloroacetate did not significantly affect the expression/activity of α-, β- or γ-secretases. In conclusion, dichloroacetate can inhibit amyloidogenic and promote non-amyloidogenic proteolysis of the amyloid precursor protein. Given the small size and blood-brain-barrier permeability of the drug, further research into its mechanism of action with respect to APP proteolysis may lead to the development of therapies for slowing the progression of Alzheimer's disease.

Dataset Information

Alzheimer's Disease "Non-amyloidogenic" p3 Peptide Revisited: A Case for Amyloid-?.

Publications

Alzheimer's Disease "Non-amyloidogenic" p3 Peptide Revisited: A Case for Amyloid-α.

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