Macroautophagy/autophagy deficit induces intracellular MAPT/tau accumulation, the hallmark pathology in Alzheimer disease (AD) and other tauopathies; however, the reverse role of MAPT accumulation in autophagy and neurodegeneration is not clear. Here, we found that overexpression of human wild-type full-length MAPT, which models MAPT pathologies as seen in sporadic AD patients, induced autophagy deficits via repression of autophagosome-lysosome fusion leading to significantly increased LC3 (microtubule-associated protein 1 light chain 3)-II and SQSTM1/p62 (sequestosome 1) protein levels with autophagosome accumulation. At the molecular level, intracellular MAPT aggregation inhibited expression of IST1 (IST1 factor associated with ESCRT-III), a positive modulator for the formation of ESCRT (the Endosomal Sorting Complex Required for Transport) complex that is required for autophagosome-lysosome fusion. Upregulating IST1 in human MAPT transgenic mice attenuated autophagy deficit with reduced MAPT aggregation and ameliorated synaptic plasticity and cognitive functions, while downregulating IST1 per se induced autophagy deficit with impaired synapse and cognitive function in naïve mice. IST1 can facilitate association of CHMP2B (charged multivesicular body protein 2B) and CHMP4B/SNF7-2 to form ESCRT-III complex, while lack of IST1 impeded the complex formation. Finally, we demonstrate that MAPT accumulation suppresses IST1 transcription with the mechanisms involving the ANP32A-regulated mask of histone acetylation. Our findings suggest that the AD-like MAPT accumulation can repress autophagosome-lysosome fusion by deregulating ANP32A-INHAT-IST1-ESCRT-III pathway, which also reveals a vicious cycle of MAPT accumulation and autophagy deficit in the chronic course of AD neurodegeneration.Abbreviations: AAV: adeno-associated virus; Aβ: β-amyloid; aCSF: artificial cerebrospinal fluid; AD: Alzheimer disease; ANP32A: acidic nuclear phosphoprotein 32 family member A; ATG: autophagy related; AVs: autophagic vacuoles; CEBPB: CCAAT enhancer binding protein beta; CHMP: charged multivesicular body protein; DMEM: Dulbecco’s modified eagle’s medium; EBSS: Earle’s balanced salt solution; EGFR: epidermal growth factor receptor; ESCRT: endosomal sorting complex required for transport; fEPSPs: field excitatory postsynaptic potentials; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GSK3B: glycogen synthase kinase 3 beta; HAT: histone acetyl transferase; HDAC: histone deacetylase; INHAT: inhibitor of histone acetyl transferase; IST1: IST1 factor associated with ESCRT-III; LAMP2: lysosomal associated membrane protein 2; LTP: long-term potentiation; MAP1LC3: microtubule associated protein 1 light chain 3; MAPT/tau: microtubule associated protein tau; MVB: multivesicular bodies; MWM: Morris water maze; PBS: phosphate-buffered saline solution; RAB7: member RAS oncogene family; SNAREs: soluble N-ethylmaleimide-sensitive factor attachment protein receptors; SQSTM1/p62: sequestosome 1

中文翻译：

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MAPT / Tau积累通过破坏IST1调控的ESCRT-III复合物的形成来抑制自噬通量：阿尔茨海默氏症神经变性的恶性循环。

巨自噬/自噬缺陷诱导细胞内MAPT / tau积累，阿尔茨海默病（AD）和其他疾病的标志性病理学；然而，MAPT积累在自噬和神经变性中的相反作用尚不清楚。在这里，我们发现人野生型全长MAPT的过表达（通过模拟散发性AD患者的MAPT病理模型）可通过以下方式诱导自噬缺陷：抑制自噬体-溶酶体融合导致自噬体积聚，从而显着增加LC3（微管相关蛋白1轻链3）-II和SQSTM1 / p62（螯合体1）蛋白水平。在分子水平上，细胞内MAPT聚集抑制了IST1（与ESCRT-III相关的IST1因子）的表达，这是自噬体-溶酶体融合所必需的ESCRT（运输所需的内体分拣复合物）复合物形成的正调节剂。上调IST1在人类MAPT转基因小鼠衰减具有减小MAPT聚集自噬赤字和改善突触可塑性和认知功能，而下调IST1本身诱导幼稚小鼠的突触和认知功能受损的自噬缺陷。IST1可以促进CHMP2B（带电荷的多囊泡体蛋白2B）与CHMP4B / SNF7-2结合形成ESCRT-III复合物，而IST1的缺乏则阻碍了复合物的形成。最后，我们证明了MAPT积累通过涉及ANP32A调节的组蛋白乙酰化掩膜的机制抑制了IST1转录。我们的研究结果表明，AD样MAPT积累可以通过调节ANP32A-INHAT-IST1-ESCRT-III通路来抑制自噬体-溶酶体融合，这也揭示了在AD神经变性的慢性过程中MAPT积累和自噬缺陷的恶性循环。缩略语：AAV：腺伴随病毒；Aβ：β-淀粉样蛋白；aCSF：人工脑脊液；AD：阿尔茨海默氏病；ANP32A：酸性核磷蛋白32家族成员A；ATG：与自噬有关；AVs：自噬空泡；CEBPB：CCAAT增强子结合蛋白β；CHMP：带电荷的多囊泡体蛋白；DMEM：Dulbecco改良的Eagle培养基；EBSS：Earle的平衡盐溶液；EGFR：表皮生长因子受体；ESCRT：运输所需的内体分选复合物；fEPSPs：野外兴奋性突触后电位；GAPDH：3-磷酸甘油醛脱氢酶；GSK3B：糖原合酶激酶3β；HAT：组蛋白乙酰转移酶；HDAC：组蛋白脱乙酰基酶；INHAT：组蛋白乙酰转移酶抑制剂；IST1：与ESCRT-III相关的IST1因子；LAMP2：溶酶体相关膜蛋白2；LTP：长期增强；MAP1LC3：微管相关蛋白1轻链3; MAPT / tau：微管相关蛋白tau；MVB：多囊泡体；MWM：莫里斯水迷宫；PBS：磷酸盐缓冲盐溶液；RAB7：RAS癌基因家族成员；SNAREs：可溶性N-乙基马来酰亚胺敏感因子附着蛋白受体；SQSTM1 / p62：螯合体1