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

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