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

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.

Rab35 controls cilium length, function and membrane composition

“…A second non-mutually exclusive possibility is that Rab35 functions at the ciliary pocket and/or nearby endosomal compartments to regulate Arl13b uptake from the periciliary membrane and subsequent sorting into recycling or degradation pathways ( Fig 9A). Indeed, the ciliary pocket is a site of endocytosis, and a role for Rab35 in promoting Arl13b uptake and subsequent degradation is consistent with our observation of increased total Arl13b levels in Rab35-depleted cells, as well as known roles for Rab35 in endocytic events such as endosomal sorting of proteins for recycling or degradation [17,[115][116][117][118][119]. An uptake function for Rab35 could act on Arl13b molecules that are either en route to the cilium or exiting from the cilium as part of a natural cycling process of Arl13b transport between ciliary and non-ciliary compartments.…”

Secretory galectin-3 induced by glucocorticoid stress triggers stemness exhaustion of hepatic progenitor cells

“…Cortisol is a hormone produced in the adrenal gland that is released in order to help the body deal with stress. Cortisol levels in the body is associated with stress including circadian rhythm disorder and anxiety disorders (11,12). These stressassociated cortisol level changes can in turn contribute to tissue damage risk and regeneration capacity by affecting the expression of molecules regulated by the damage-induced phenotypes and the state of progenitor cells in niche, thus altering cell and tissue function.…”

“…Among important factors influencing tissue damage and aging, glucocorticoids signaling acts as a driver of stress-related damage. Psychosocial stress, circadian rhythm disorder, anxiety disorders, and abnormal metabolism always cause stress response changes including glucocorticoids pathway (10)(11)(12)(13)(14). Studies further suggest that stress-related phenotypes may together confer disease by increasing tissue aging risk (15), but the underlying mechanism are poorly understood.…”

The role of stress in the pathogenesis of Alzheimer’s disease

“…Важнейшим молекулярным признаком БА является накопление тау-белка в виде нейрофибриллярных клубков, обладающих нейротоксичностью (Iqbal et al 2010). Одно из недавних исследований выявило, что в норме тау подвергается эндосомной деградации (Vaz-Silva et al 2018). Показано, что нокаут гена, кодирующего малую гуанозинтрифосфат гидролазу (ГТФазу) Rab35, играющую ключевую роль в регуляции сортировки тау на пути к лизосомам, значительно замедляет его деградацию.…”