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.
Highlights
Neurofibrillary tangles (NFT), which consist of extensively phosphorylated tau, and senile plaques (SP), which consist of amyloid β protein (Aβ), are pathological hallmarks of Alzheimer’s disease (AD)
Dysfunction of autophagy, which disrupts the effective clearance of misfolded proteins and cytoplasmic oligomers, has been observed in many neurodegenerative disorders, including AD, Parkinson’s disease, amyotrophic lateral sclerosis, and Huntington’s disease
Regulation of autophagy may be favorable in the prevention and therapeutics of AD by preventing tau aggregation
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Neurofibrillary tangles (NFT), which consist of extensively phosphorylated tau, and senile plaques (SP), which consist of amyloid β protein (Aβ), are pathological hallmarks of Alzheimer’s disease (AD). The free tau forms aggregates, known as tau oligomers (Figure 1). Further aggregation of tau oligomers forms NFT. Tau cleavage at C terminus can be the factor that accelerates tau aggregation because the C terminus of tau inhibits tau aggregation (Figure 1A) [6] Another important factor that leads to tau aggregation is the disturbance of tau clearance. We describe the process by which the autophagy lysosome system degrades tau protein,ofincluding aggregated tau, and the possibility of autophagy regulaAs the mechanisms tau clearance, two pathways have been proposed, the ubiquitin proteasome system and the autophagy lysosome system. Tau Protein or 2) and microtubule-binding repeat domains (3R, or 4R), which produce 6 isoforms, 4
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