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

Amyloid-beta (A beta) 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 beta, displays enhanced aggregation rates. Our findings highlight the solubilizing effect of the Nterminus of A beta 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 beta-secretase pathway of AD, given that the a- secretase pathway is also amyloidogenic.