Endolysosomal degradation of Tau and its role in glucocorticoid-driven hippocampal malfunction

João Vaz-Silva, Patrícia Gomes, Qi Jin, Mei Zhu, Viktoriya Zhuravleva, Sebastian Quintremil, Torcato Meira, Joana Silva, Chrysoula Dioli, Carina Soares-Cunha, Nikolaos P. Daskalakis, Nuno Sousa, Ioannis Sotiropoulos, Clarissa L. Waites

Research output: Contribution to journalArticlepeer-review

69 Scopus citations

Abstract

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.

Original languageEnglish
Article numbere99084
JournalEMBO Journal
Volume37
Issue number20
DOIs
StatePublished - 15 Oct 2018
Externally publishedYes

Keywords

  • ESCRT
  • Rab35
  • Tau
  • endolysosomal
  • glucocorticoid

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