中文摘要：

Microglia 玩在由降级的 A 的清理的一个枢轴的角色他们在 lysosomes，在 Alzheimers 疾病(广告) 阻止淀粉的匾致病。最近的证据建议那个 lysosomal 机能障碍导致有毒的蛋白质总数的不够的消除。我们测试了是否与抄写因素 EB (TFEB ) 提高 lysosomal 功能，必要管理者 modulating lysosomal 小径，将在 microglia 支持一个清理。这里，我们证明 TFEB 的那 microglial 表情便于降级和还原剂扔了的纤丝状的 A (fA ) 淀粉的匾，它被 TFEB 的 deacetylation 进一步提高。用集体 spectrometry 分析，我们第一证实了是的 acetylation 一以前 TFEB 的 unreported 修正并且发现那 SIRT1 直接交往了与并且在离氨酸残余 116 点的 deacetylated TFEB。随后，当 TFEB 被击倒时， SIRT1 overexpression 由 TFEB 下游的目标的 upregulating transcriptional 层次提高了 lysosomal 功能和 fA 降级，它能被禁止。而且，在在 microglia 变异的 K116R 的 deacetylated TFEB 的 overexpression 由刺激 lysosomal 生物的续生说加速了细胞内部的 fA 降级并且极大地在 APP/PS1 转基因的老鼠的大脑片减少了扔的淀粉的匾。我们的调查结果表明 TFEB 的 deacetylation 能调整 lysosomal 生物的续生说和 fA 降级，为 attenuating 使 TFEB 的 microglial 激活成为可能的策略在广告的淀粉的匾免职。

英文摘要：

Microglia play a pivotal role in clearance of Aβ by degrading them in lysosomes, countering amyloid pla- que pathogenesis in Alzheimer＇s disease （AD）. Recent evidence suggests that lysosomal dysfunction leads to insufficient elimination of toxic protein aggregates. We tested whether enhancing lysosomal function with transcription factor EB （TFEB）, an essential regulator modulating lysosomal pathways, would promote Aβ clearance in microglia. Here we show that microglial expression of TFEB facilitates fibrillar Aβ （fAβ） degra- dation and reduces deposited amyloid plaques, which are further enhanced by deacetylation of TFEB. Using mass spectrometry analysis, we firstly confirmed acetylation as a previously unreported modification of TFEB and found that SIRT1 directly interacted with and deacetylated TFEB at lysine residue 116. Subsequently, SIRT1 overexpression enhanced lysosomal function and fAβ degradation by upregulating transcriptional levels of TFEB downstream targets, which could be inhibited when TFEB was knocked down. Furthermore, overexpression of deacetylated TFEB at K116R mutant in microglia accelerated intracellular fAβ degradation by stimulating lysosomal biogenesis and greatly reduced the deposited amyloid plaques in the brain slices of APPIPS1 transgenic mice. Our findings reveal that deacetylaUon of TFEB could regulate lysosomal biogenesis and fAβ degradation, making microglial activation of TFEB a possible strategy for attenuating amyloid plaque deposition in AD.