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
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DOI：
10.1021/acschemneuro.0c00160
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发表时间：
2020-06-03
影响因子：
5
通讯作者：
Raskatov, Jevgenij A.
中科院分区：
文献类型：
--
作者：
Kuhn, Ariel J.;Abrams, Benjamin S.;Raskatov, Jevgenij A.
淀粉样β蛋白(Aβ)是一种内在的无序多肽，被认为在阿尔茨海默病(AD)中起着重要作用。它一直是大多数AD治疗努力的目标，在临床试验中一再失败。一种更主要的多肽片段，通过对淀粉样前体蛋白的替代加工而形成，是p3肽。P3受到的关注很少，这可能是由于AD领域的普遍观点，即它是“非淀粉样变性的”。通过探索这种多肽的自组装，我们发现p3聚集形成低聚物和纤维，与Aβ相比，显示出更高的聚集率。我们的发现突出了Aβ末端的增溶作用，以及通过C端疏水多肽界面形成的结构的有利形成。基于我们的发现，我们建议重新评估目前仅针对AD的β-分泌酶途径的治疗方法，因为α-分泌酶途径也是淀粉样变性的致病因素。
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.