Section of Cell Biology and Pathology, Department of Alzheimer's Disease Research, Center for Development of Advanced Medicine for Dementia, Obu, Aichi, Japan; Division of Biosignaling, Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Chiba, Japan.
Tsukuba Primate Research Center, National Institutes of Biomedical Innovation, Health and Nutrition, Tsukuba, Ibaraki, Japan.
Neurobiol Aging. 2021 Oct;106:268-281. doi: 10.1016/j.neurobiolaging.2021.06.022. Epub 2021 Jul 5.
Aβ metabolism in the brain is mediated by endocytosis, one part of the intracellular membrane trafficking system. We previously showed that aging attenuates the interaction of dynein with dynactin, which disrupts the endosomal/lysosomal trafficking pathway involved in Aβ metabolism, resulting in intracellular accumulation of Aβ. Several studies have shown that in Alzheimer's disease (AD), intraneuronal accumulation of Aβ precedes extracellular Aβ depositions. However, it is unclear what accounts for this transition from intracellular to extracellular depositions. Accumulating evidence suggest that autophagy has an important role in AD pathology, and we observed that autophagy-related protein levels began to decrease before amyloid plaque formation in cynomolgus monkey brains. Surprisingly, experimental induction of autophagosome formation in Neuro2a cells significantly increased intracellular Aβ and decreased extracellular release of Aβ, accompanied by the prominent reduction of extracellular vesicle (EV) secretion. RNAi study confirmed that EV secretion affected intracellular and extracellular Aβ levels, and siRNA-induced downregulation of autophagosome formation enhanced EV secretion to ameliorate intracellular Aβ accumulation induced by dynein knockdown. In aged cynomolgus monkeys, Aβ levels in EV/intraluminal membrane vesicle (ILV)-rich fractions isolated from temporal lobe parenchyma were drastically increased. Moreover, EV/ILV marker proteins overlapped spatially with amyloid plaques. These findings suggest that EV would be an important carrier of Aβ in brain and abnormal accumulation of Aβ in EVs/ILVs may be involved in the transition of age-dependent Aβ pathology.
脑内 Aβ 的代谢是由内吞作用介导的，内吞作用是细胞内膜运输系统的一部分。我们之前的研究表明，衰老会减弱动力蛋白与动力蛋白激活蛋白复合物的相互作用，从而破坏参与 Aβ 代谢的内体/溶酶体运输途径，导致 Aβ 在细胞内积累。几项研究表明，在阿尔茨海默病（AD）中，Aβ 在神经元内的积累先于细胞外 Aβ 沉积。然而，尚不清楚这一从细胞内到细胞外沉积的转变是由什么引起的。越来越多的证据表明自噬在 AD 病理中具有重要作用，我们观察到自噬相关蛋白水平在食蟹猴大脑中淀粉样斑块形成之前开始下降。令人惊讶的是，实验诱导 Neuro2a 细胞中自噬体的形成显著增加了细胞内 Aβ，并减少了细胞外 Aβ 的释放，同时显著减少了细胞外囊泡（EV）的分泌。RNAi 研究证实 EV 分泌会影响细胞内和细胞外 Aβ 水平，并且通过 siRNA 诱导的自噬体形成下调增强了 EV 分泌，从而改善了因动力蛋白敲低而导致的细胞内 Aβ 积累。在老年食蟹猴中，从颞叶实质中分离出的富含 EV/内室膜泡（ILV）的级分中 Aβ 水平显著增加。此外，EV/ILV 标志物蛋白在空间上与淀粉样斑块重叠。这些发现表明 EV 可能是脑内 Aβ 的重要载体，EV/ILV 中 Aβ 的异常积累可能参与了年龄依赖性 Aβ 病理的转变。
