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.

大脑中的 Aβ 代谢由内吞作用介导，内吞作用是细胞内膜运输系统的一部分。我们之前表明，衰老会减弱动力蛋白与动力蛋白的相互作用，这会破坏参与 Aβ 代谢的内体/溶酶体运输途径，导致 Aβ 的细胞内积累。多项研究表明，在阿尔茨海默病 (AD) 中，Aβ 的神经元内积累先于细胞外 Aβ 沉积。然而，尚不清楚是什么解释了这种从细胞内沉积到细胞外沉积的转变。越来越多的证据表明自噬在 AD 病理学中具有重要作用，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。出奇，Neuro2a 细胞中自噬体形成的实验诱导显着增加了细胞内 Aβ 并减少了 Aβ 的细胞外释放，伴随着细胞外囊泡 (EV) 分泌的显着减少。RNAi 研究证实 EV 分泌影响细胞内和细胞外 Aβ 水平，siRNA 诱导的自噬体形成下调增强了 EV 分泌，以改善动力蛋白敲低诱导的细胞内 Aβ 积累。在老年食蟹猴中，从颞叶实质中分离出的富含 EV/腔内膜囊泡 (ILV) 的组分中的 Aβ 水平急剧增加。此外，EV/ILV 标记蛋白与淀粉样斑块在空间上重叠。