Alsaqati Mouhamed, Thomas Rhian S, Kidd Emma J
School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Redwood Building, King Edward VII Avenue, Cardiff CF10 3NB, UK.
Aging Brain. 2023 Jun 21;4:100084. doi: 10.1016/j.nbas.2023.100084. eCollection 2023.
Amyloid-beta (Aβ) is produced from amyloid precursor protein (APP) primarily after APP is internalised by endocytosis and clathrin-mediated endocytic processes are altered in Alzheimer's disease (AD). There is also evidence that cholesterol and flotillin affect APP endocytosis. We hypothesised that endocytic protein expression would be altered in the brains of people with AD compared to non-diseased subjects which could be linked to increased Aβ generation. We compared protein expression in frontal cortex samples from men with AD compared to age-matched, non-diseased controls. Soluble and insoluble Aβ40 and Aβ42, the soluble Aβ42/Aβ40 ratio, βCTF, BACE1, presenilin-1 and the ratio of phosphorylated:total GSK3β were significantly increased while the insoluble Aβ42:Aβ40 ratio was significantly decreased in AD brains. Total and phosphorylated tau were markedly increased in AD brains. Significant increases in clathrin, AP2, PICALM isoform 4, Rab-5 and caveolin-1 and 2 were seen in AD brains but BIN1 was decreased. However, using immunohistochemistry, caveolin-1 and 2 were decreased. The results obtained here suggest an overall increase in endocytosis in the AD brain, explaining, at least in part, the increased production of Aβ during AD.
淀粉样蛋白β（Aβ）主要在淀粉样前体蛋白（APP）通过内吞作用内化后产生，且在阿尔茨海默病（AD）中网格蛋白介导的内吞过程会发生改变。也有证据表明胆固醇和小窝蛋白影响APP的内吞作用。我们推测，与非患病受试者相比，AD患者大脑中的内吞蛋白表达会发生改变，这可能与Aβ生成增加有关。我们比较了AD男性患者与年龄匹配的非患病对照者额叶皮质样本中的蛋白表达。在AD大脑中，可溶性和不可溶性Aβ40和Aβ42、可溶性Aβ42/Aβ40比值、β分泌酶裂解片段（βCTF）、β分泌酶1（BACE1）、早老素1以及磷酸化GSK3β与总GSK3β的比值均显著升高，而不可溶性Aβ42:Aβ40比值则显著降低。AD大脑中总tau蛋白和磷酸化tau蛋白均明显增加。在AD大脑中可见网格蛋白、衔接蛋白2（AP2）、磷脂酰肌醇结合网格蛋白装配蛋白亚型4（PICALM isoform 4）、小G蛋白Rab-5以及小窝蛋白-1和2显著增加，但桥联整合膜蛋白1（BIN1）减少。然而，通过免疫组织化学检测发现小窝蛋白-1和2减少。此处获得的结果表明AD大脑中的内吞作用总体增加，这至少部分解释了AD期间Aβ生成增加的原因。
