Aging induces abnormal accumulation of Aβ in extracellular vesicle and/or intraluminal membrane vesicle-rich fractions in nonhuman primate brain

[摘要] A beta 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 A beta metabolism, resulting in intracellular accumulation of A beta. Several studies have shown that in Alzheimer's disease (AD), intraneuronal accumulation of A beta precedes extracellular A beta 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 A beta and decreased extracellular release of A beta, accompanied by the prominent reduction of extracellular vesicle (EV) secretion. RNAi study confirmed that EV secretion affected intracellular and extracellular A beta levels, and siRNA-induced downregulation of autophagosome formation enhanced EV secretion to ameliorate intracellular A beta accumulation induced by dynein knockdown. In aged cynomolgus monkeys, AP 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 A beta in brain and abnormal accumulation of A beta in EVs/ILVs may be involved in the transition of age-dependent A beta pathology. (C) 2021 The Author(s). Published by Elsevier Inc.

[发布日期] 2021-10-01

[关键词] A beta pathology;Aging;Extracellular vesicles;Intraluminal membrane vesicles;Nonhuman primates