The Alzheimer's Disease "non-amyloidogenic" p3 peptide revisited: a case for Amyloid-α.
2020
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 N-terminus 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 α-
secretase pathway is also amyloidogenic.
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