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 i...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.展开更多
SiCp/Al composites have excellent comprehensive properties and have been widely used in aerospace,automotive industry and other fields.Due to the huge difference in performance between SiC particles and matrix alloys,...SiCp/Al composites have excellent comprehensive properties and have been widely used in aerospace,automotive industry and other fields.Due to the huge difference in performance between SiC particles and matrix alloys,traditional fusion welding methods are difficult to meet the join requirements of SiCp/Al composites.Friction stir joining(friction stir welding),as a solid phase joining process,has been proved to be a new technology with fine prospect in joining SiCp/Al composites compared with fusion welding process.Although some progress has been made in recent years,there are still full of challenges.In this paper,the research status of friction stir joining of SiCp/Al composites in recent years is expatiated,including the weldability of SiCp/Al composites,the macrostructure and the microstructure of joints,mechanical properties of joints,and tool wear and monitoring.Furthermore,the existing challenges of friction stir joining of SiCp/Al composites are summarized and the future development directions are prospected.展开更多
文摘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.
基金supported by the National Natural Science Foundation of China(No.51675270)the Postgraduate Research&Practice Innovation Program of Jiangsu Province(No.KYCX17_0241)the China Postdoctoral Science Foundation(No.2016M600411)。
文摘SiCp/Al composites have excellent comprehensive properties and have been widely used in aerospace,automotive industry and other fields.Due to the huge difference in performance between SiC particles and matrix alloys,traditional fusion welding methods are difficult to meet the join requirements of SiCp/Al composites.Friction stir joining(friction stir welding),as a solid phase joining process,has been proved to be a new technology with fine prospect in joining SiCp/Al composites compared with fusion welding process.Although some progress has been made in recent years,there are still full of challenges.In this paper,the research status of friction stir joining of SiCp/Al composites in recent years is expatiated,including the weldability of SiCp/Al composites,the macrostructure and the microstructure of joints,mechanical properties of joints,and tool wear and monitoring.Furthermore,the existing challenges of friction stir joining of SiCp/Al composites are summarized and the future development directions are prospected.