The role of autophagy in degrading amyloid β protein and tau protein

Tadanori Hamano, Tomohisa Yamaguchi, Hirohito Sasaki, Rei Asano, Soichi Enomoto

Department of Neurology, Faculty of Medical Sciences, University of Fukui

Senile plaques （SPs） consist of amyloid β protein （Aβ） and neurofibrillary tangles, which consist of highly phosphorylated tau protein, are pathological hallmarks of Alzheimer's disease （AD）.　In swollen axons, many autophagic vacuoles （Avs） are observed around SP in the AD brain.　This suggests that autophagy function is disturbed in AD.　Aβ was colocalized with AVs of dystrophic neurites in mouse mode of AD.　Autophagy associated protein Beclin1 depletion deteriorated Aβ deposition in mouse model of AD.　Rapamycin treatment at the early stage, not late stage of 3xTg AD mouse model ameliorated Aβ deposition, as well as cognitive decline.　These results strongly suggested that Aβ is degraded via autophagy.　As the degradation mechanisms of tau, we used a neuronal cellular model of tauopathy, which has wild type tau （4R0N） to explore the effects of the autophagy and lysosomal inhibitor chloroquine and autophagy inhibitor 3 methyladenine （3MA）.　Chloroquine, and 3MA markedly increased tau accumulation.　Thus, autophagy lysosome 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, many autophagy modulators, including mTORC1 inhibitor rapamycin and its analogues, torehalose, IMPase inhibitor lithium, statin, metformin, clonidine, curcumin, nicotinamide, bexarotene, and TFEB activator fisetin have been proposed.　As a therapeutic strategy, autophagic modulation may be the next target of AD therapeutics.
Keywords:autophagy;Alzheimer's disease;amyloid β protein;tau protein;mTORC1

Address correspondence to Dr. Tadanori Hamano, Department of Neurology, Faculty of Medical Sciences, University of Fukui （23-3 Matsuokashimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui 910-1193, Japan）