Dept of Physiology, UT Southwestern Medical Center, Dallas, TX, 75390, USA.
Dept of Physiology, UT Southwestern Medical Center, Dallas, TX, 75390, USA; Laboratory of Molecular Neurodegeneration, St Petersburg State Polytechnical Universty, St Petersburg, 195251, Russian Federation.
Biochem Biophys Res Commun. 2024 Nov 19;734:150611. doi: 10.1016/j.bbrc.2024.150611. Epub 2024 Aug 29.
Proteolytic processing of amyloid precursor protein (APP) plays a critical role in the pathogenesis of Azheimer's disease (AD). Sequential cleavage of APP by β and γ secretases leads to generation of Aβ40 (non-amyloidogenic) and Aβ42 (amyloidogenic) peptides. Despite intense studies, the biological function of these peptides and the mechanism of Aβ42 toxicity is poorly understood. In the previous publications we proposed that association of Aβ peptides with the endosomal membranes may have important implications for pathogenesis of AD (Kim and Bezprozvanny, IJMS, 2021, vol 22, 13600; Kim and Bezprozvanny, IJMS, 2023, vol 24, 2092). To understand potential biological importance of such interaction, we focused on the region of Aβ peptides involved in peri-membrane association (E682 to N698). We discovered that association of this region with the membranes is reminiscent of several known anti-microbial peptides (AMP) such as PA13, Aurein1.2 and BP100. Our analysis further revealed that energy of peri-membrane association of Aβ40 is significantly weaker than for Aβ42 or AMP peptides, but it can be increased in the presence of non-amyloidogenic FAD mutations or in the presence of cholesterol in the membrane. Based on similarity with established mechanism of action of AMP peptides, we propose that Aβ peptides affect the curvature of endosomal membranes and shift the balance between endosomal recycling to plasma membrane and late endosomal/lysosomal pathway. We further propose that these effects are enhanced as a result of non-amyloidogenic FAD mutations in the sequence of Aβ peptides or in the presence of cholesterol in the membrane. The proposed model provides potential mechanistic explanation to synaptic defects induced by increased levels of Aβ42, by non-amyloidogenic FAD mutations in APP and by age-related increase in the levels of cholesterol in the brain.
淀粉样前体蛋白（APP）的蛋白水解加工在阿尔茨海默病（AD）的发病机制中起着关键作用。APP 通过β 和 γ 分泌酶的连续切割导致 Aβ40（非淀粉样形成）和 Aβ42（淀粉样形成）肽的产生。尽管进行了深入研究，但这些肽的生物学功能以及 Aβ42 毒性的机制仍知之甚少。在之前的出版物中，我们提出 Aβ 肽与内体膜的结合可能对 AD 的发病机制有重要影响（Kim 和 Bezprozvanny，IJMS，2021 年，第 22 卷，13600；Kim 和 Bezprozvanny，IJMS，2023 年，第 24 卷，2092）。为了了解这种相互作用的潜在生物学重要性，我们专注于与膜周围结合相关的 Aβ 肽区域（E682 至 N698）。我们发现，该区域与膜的结合类似于几种已知的抗微生物肽（AMP），如 PA13、Aurein1.2 和 BP100。我们的分析进一步表明，Aβ40 与膜的周边结合能显著弱于 Aβ42 或 AMP 肽，但在非淀粉样形成的 FAD 突变或膜中胆固醇存在的情况下，其结合能增加。基于与已建立的 AMP 肽作用机制的相似性，我们提出 Aβ 肽会影响内体膜的曲率，并改变内体循环到质膜和晚期内体/溶酶体途径之间的平衡。我们进一步提出，由于 Aβ 肽序列中的非淀粉样形成的 FAD 突变或膜中胆固醇的存在，这些影响会增强。所提出的模型为 Aβ42 水平升高、APP 中非淀粉样形成的 FAD 突变以及大脑中胆固醇水平随年龄增长而增加所导致的突触缺陷提供了潜在的机制解释。
