Aging induces abnormal accumulation of Aβ in extracellular vesicle and/or intraluminal membrane vesicle-rich fractions in nonhuman primate brain
Aging induces abnormal accumulation of Aβ in extracellular vesicle and/or intraluminal membrane vesicle-rich fractions in nonhuman primate brain
复制标题
衰老会导致非人灵长类动物大脑中细胞外囊泡和/或腔内膜囊泡丰富部分中 Aβ 的异常积累
DOI：
10.1016/j.neurobiolaging.2021.06.022
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发表时间：
2021
影响因子：
4.2
通讯作者：
Kimura Nobuyuki
中科院分区：
文献类型：
--
作者：
Koinuma Shingo;Shimozawa Nobuhiro;Yasutomi Yasuhiro;Kimura Nobuyuki
脑中的Aβ代谢由胞吞作用介导，胞吞作用是细胞内膜运输系统的一部分。我们先前表明，衰老减弱了动力蛋白与动力肌动蛋白的相互作用，这破坏了参与Aβ代谢的内体/溶酶体运输途径，导致Aβ在细胞内蓄积。几项研究表明，在阿尔茨海默病（AD）中，神经元内Aβ蓄积先于细胞外Aβ沉积。然而，目前还不清楚是什么原因导致这种从细胞内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，我们观察到食蟹猴脑中自噬相关蛋白水平在淀粉样斑块形成之前开始下降。令人惊讶的是，Neuro 2a细胞中自噬体形成的实验诱导显著增加了细胞内Aβ并减少了Aβ的细胞外释放，同时伴有细胞外囊泡（EV）分泌的显著减少。RNAi研究证实EV分泌影响细胞内和细胞外Aβ水平，siRNA诱导的自噬体形成的下调促进EV分泌，从而改善动力蛋白敲低诱导的细胞内Aβ积聚。在老年食蟹猴中，从颞叶实质分离的EV/管腔内膜囊泡（ILV）富集组分中的Aβ水平急剧升高。此外，EV/ILV标记蛋白在空间上与淀粉样斑块重叠。提示EV是Aβ在脑内的重要载体，Aβ在EV/ILV中的异常蓄积可能参与了Aβ的年龄依赖性病理转变。
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.
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DOI：
10.1007/978-1-4939-2569-8_1
发表时间：
2015
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Li G;Marlin MC
通讯作者：
Marlin MC
关于使用非人类灵长类动物进行动物实验的指导原则
DOI：
10.2354/psj.2.109
发表时间：
1986
期刊：
Primate Research
影响因子：
--
作者：
S. Honjo
通讯作者：
S. Honjo
影响因子：
4
作者：
Colombo, Marina;Moita, Catarina;Raposo, Graca
通讯作者：
Raposo, Graca
影响因子：
12.7
作者：
Wegiel J;Kuchna I;Nowicki K;Frackowiak J;Mazur-Kolecka B;Imaki H;Wegiel J;Mehta PD;Silverman WP;Reisberg B;Deleon M;Wisniewski T;Pirttilla T;Frey H;Lehtimäki T;Kivimäki T;Visser FE;Kamphorst W;Potempska A;Bolton D;Currie JR;Miller DL
通讯作者：
Miller DL
影响因子：
0.7
作者：
Nakamura, S;Nakayama, H;Yoshikawa, Y
通讯作者：
Yoshikawa, Y