Department of Physiology, Sungkyunkwan University School of Medicine, Suwon 16419, Korea.
Molecules. 2020 Nov 24;25(23):5490. doi: 10.3390/molecules25235490.
Amyloid precursor protein (APP) at the plasma membrane is internalized via endocytosis and delivered to endo/lysosomes, where neurotoxic amyloid-β (Aβ) is produced via β-, γ-secretases. Hence, endocytosis plays a key role in the processing of APP and subsequent Aβ generation. β-, γ-secretases as well as APP are localized in cholesterol-enriched lipid raft microdomains. However, it is still unclear whether lipid rafts are the site where APP undergoes endocytosis and whether cholesterol levels affect this process. In this study, we found that localization of APP in lipid rafts was increased by elevated cholesterol level. We also showed that increasing or decreasing cholesterol levels increased or decreased APP endocytosis, respectively. When we labeled cell surface APP, APP localized in lipid rafts preferentially underwent endocytosis compared to nonraft-localized APP. In addition, APP endocytosis from lipid rafts was regulated by cholesterol levels. Our results demonstrate for the first time that cholesterol levels regulate the localization of APP in lipid rafts affecting raft-dependent APP endocytosis. Thus, regulating the microdomain localization of APP could offer a new therapeutic strategy for Alzheimer's disease.
淀粉样前体蛋白（APP）位于质膜上，通过内吞作用内化，并被递送至内体/溶酶体，在那里通过β-、γ-分泌酶产生神经毒性淀粉样β（Aβ）。因此，内吞作用在 APP 的加工和随后的 Aβ生成中起着关键作用。β-、γ-分泌酶以及 APP 都定位于富含胆固醇的脂筏微域中。然而，脂筏是否是 APP 发生内吞作用的部位以及胆固醇水平是否影响这一过程仍不清楚。在这项研究中，我们发现胆固醇水平的升高会增加 APP 在脂筏中的定位。我们还表明，胆固醇水平的增加或减少分别增加或减少了 APP 的内吞作用。当我们标记细胞表面的 APP 时，与非脂筏定位的 APP 相比，定位于脂筏中的 APP 优先发生内吞作用。此外，脂筏中的 APP 内吞作用受胆固醇水平调节。我们的结果首次表明，胆固醇水平调节 APP 在脂筏中的定位，从而影响依赖脂筏的 APP 内吞作用。因此，调节 APP 的微域定位可能为阿尔茨海默病提供一种新的治疗策略。
