As neurons age, they show a decrease in their ability to degrade proteins and membranes. Because undegraded material is a source of toxic products, defects in degradation are associated with reduced cell function and survival. However, there are very few dead neurons in the aging brain, suggesting the action of compensatory mechanisms. We show in this work that ageing neurons in culture show large multivesicular bodies (MVBs) filled with intralumenal vesicles (ILVs) and secrete more small extracellular vesicles than younger neurons. We also show that the high number of ILVs is the consequence of the accumulation of cholesterol in MVBs, which in turn is due to decreased levels of the cholesterol extruding protein NPC1. NPC1 down-regulation is the consequence of a combination of upregulation of the NPC1 repressor microRNA 33, and increased degradation, due to Akt-mTOR targeting of NPC1 to the phagosome. Although releasing more exosomes can be beneficial to old neurons, other cells, neighbouring and distant, can be negatively affected by the waste material they contain.

中文翻译：

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通过NPC1介导的内体胆固醇积累增加体外老化神经元的外泌体分泌。

随着神经元老化，它们降解蛋白质和细胞膜的能力会下降。由于未降解的材料是有毒产品的来源，因此降解缺陷与细胞功能和存活率降低有关。然而，衰老大脑中死亡的神经元很少，这表明代偿机制的作用。我们在这项工作中表明，培养中的老化神经元显示出充满腔内囊泡 (ILV) 的大型多泡体 (MVB)，并且比年轻的神经元分泌更多的小细胞外囊泡。我们还表明，大量 ILV 是 MVB 中胆固醇积累的结果，而这又是由于胆固醇挤出蛋白 NPC1 的水平降低所致。NPC1 下调是 NPC1 阻遏物 microRNA 33 上调组合的结果，由于 Akt-mTOR 将 NPC1 靶向吞噬体，因此降解增加。尽管释放更多的外泌体对老神经元有益，但邻近和远处的其他细胞可能会受到它们所含废物的负面影响。