Autophagy and Tau Protein

Abstract

Neurofibrillary tangles, which consist of highly phosphorylated tau protein, and senile plaques (SPs) are pathological hallmarks of Alzheimer’s disease (AD). In swollen axons, many autophagic vacuoles are observed around SP in the AD brain. This suggests that autophagy function is disturbed in AD. We used a neuronal cellular model of tauopathy (M1C cells), which harbors wild type tau (4R0N), to assess the effects of the lysosomotrophic agent NH4Cl, and autophagy inhibitors chloroquine and 3 methyladenine (3MA). It was found that chloroquine, NH4Cl and 3MA markedly increased tau accumulation. Thus, autophagy lysosomal system disturbances disturbed the degradation mechanisms of tau protein. Other studies also revealed that tau protein, including aggregated tau, is degraded via the autophagy lysosome system. Phosphorylated and C terminal truncated tau were also reported to disturb autophagy function. As a therapeutic strategy, autophagy upregulation was suggested. Thus far, as autophagy modulators, rapamycin, mTOCR1 inhibitor and its analogues, lithium, metformin, clonidine, curcumin, nicotinamide, bexaroten, and torehalose have been proposed. As a therapeutic strategy, autophagic modulation may be the next target of AD therapeutics.

Presenilin-1 F105C mutation leads to tau accumulation in human neurons via the Akt/mTORC1 signaling pathway

“…Previous studies demonstrated that soluble tau is cleared by endosomal microautophagy and chaperon-mediated autophagy, while intracellular insoluble tau is degraded by macroautophagy [ 21 – 24 ]. However, hyperphosphorylated tau still accumulates in PS1 F105C neurons, revealing that autophagy system is insensitive to tau accumulation in PS1 F105C neurons.…”

A Tau Pathogenesis-Based Network Pharmacology Approach for Exploring the Protections of Chuanxiong Rhizoma in Alzheimer’s Disease

“…The clearance of physiological and pathological tau is mainly mediated by the ubiquitin proteasome system and autophagy/lysosomal degradation pathway. In AD patients, the neuronal lysosome system was dysregulated ( Sundelof et al, 2010 ; Wang X. M. et al, 2021 ; Liu et al, 2021 ; Hamano et al, 2021 ). The results of this study show that CR promotes the degradation of pathological tau mainly through the lysosome system rather than the proteasome system.…”

Dietary Supplements and Natural Products: An Update on Their Clinical Effectiveness and Molecular Mechanisms of Action During Accelerated Biological Aging

“…It suppresses inflammation and promotes vasorelaxation in rheumatoid arthritis and hypertension, respectively ( Su et al, 2020 ; Behl et al, 2021 ; Mokgalaboni et al, 2021 ). So far, several action mechanisms for curcumin in biological aging have been proposed, including mitophagy/autophagy induction, inflammation and oxidation suppression, AMPK and SIRT1 pathway stimulation, senescence, mTOR inhibition, and mitochondrial function maintenance ( Hamano et al, 2021 ; Zia et al, 2021 ; Dhapola et al, 2022 ). This broad range of effects of curcumin indicates that curcumin or its semi-synthetic derivatives target or bind to numerous intracellular macromolecules or modulate transcriptional responses to influence diverse aging-related pathways.…”