Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 22, Issue 14, Pages -Publisher
MDPI
DOI: 10.3390/ijms22147475
Keywords
autophagy; Alzheimer's disease; tau protein; amyloid beta protein; autophagic vacuoles; mTORC1
Funding
- JSPS KAKENHI [19K07909]
- University of Fukui [LSI20306]
- Grants-in-Aid for Scientific Research [19K07909] Funding Source: KAKEN
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Neurofibrillary tangles and senile plaques are pathological hallmarks of Alzheimer's disease, with autophagy disturbances being implicated in tau protein accumulation. Therapeutic strategies focusing on autophagic modulation may hold promise in AD treatment.
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.
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