期刊
EMBO JOURNAL
卷 37, 期 20, 页码 -出版社
WILEY
DOI: 10.15252/embj.201899084
关键词
endolysosomal; ESCRT; glucocorticoid; Rab35; Tau
资金
- NIH [R01NS080967, R21MH104803]
- Portuguese Foundation for Science & Technology (FCT) [PD/BD/105938/2014, PD/BD/113700/2015]
- FCT [IF/01799/2013, PEst-C/SAU/LA0026/2013]
- Portuguese North Regional Operational Program (ON.2) under the National Strategic Reference Framework (QREN), through the European Regional Development Fund (FEDER)
- European Regional Development Fund COMPETE [FCOMP-01-0124-FEDER-037298]
- Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER) [NORTE-01-0145-FEDER-000013]
- Fundação para a Ciência e a Tecnologia [PD/BD/113700/2015, PD/BD/105938/2014] Funding Source: FCT
Emerging studies implicate Tau as an essential mediator of neuronal atrophy and cognitive impairment in Alzheimer's disease (AD), yet the factors that precipitate Tau dysfunction in AD are poorly understood. Chronic environmental stress and elevated glucocorticoids (GC), the major stress hormones, are associated with increased risk of AD and have been shown to trigger intracellular Tau accumulation and downstream Tau-dependent neuronal dysfunction. However, the mechanisms through which stress and GC disrupt Tau clearance and degradation in neurons remain unclear. Here, we demonstrate that Tau undergoes degradation via endolysosomal sorting in a pathway requiring the small GTPase Rab35 and the endosomal sorting complex required for transport (ESCRT) machinery. Furthermore, we find that GC impair Tau degradation by decreasing Rab35 levels, and that AAV-mediated expression of Rab35 in the hippocampus rescues GC-induced Tau accumulation and related neurostructural deficits. These studies indicate that the Rab35/ESCRT pathway is essential for Tau clearance and part of the mechanism through which GC precipitate brain pathology.
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