Celastrol enhances transcription factor EB (TFEB)-mediated autophagy and mitigates Tau pathology:Implications for Alzheimer's disease therapy

Alzheimer's disease(AD),characterized by the accumulation of protein aggregates including phosphorylated Tau aggregates,is the most common neurodegenerative disorder with limited therapeutic agents.Autophagy plays a critical role in the degradation of phosphorylated Tau aggregates,and transcription factor EB(TFEB)is a master regulator of autophagy and lysosomal biogenesis.Thus,small-molecule autophagy enhancers targeting TFEB hold promise for AD therapy.Here,we found that celastrol,an active ingredient isolated from the root extracts of Tripterygium wilfordii(Lei Gong Teng in Chinese)enhanced TFEB-mediated autophagy and lysosomal biogenesis in vitro and in mouse brains.Importantly,celastrol reduced phosphorylated Tau aggregates and attenuated memory dysfunction and cognitive deficits in P301S Tau and 3xTg mice,two commonly used AD animal models.Mechanistical studies suggest that TFEB-mediated autophagy-lysosomal pathway is responsible for phosphorylated Tau degradation in response to celastrol.Overall,our findings indicate that Celastrol is a novel TFEB activator that promotes the degradation of phosphorylated Tau aggregates and improves memory in AD animal models.Therefore,Celastrol shows potential as a novel agent for the treatment and/or prevention of AD and other tauopathies.

Corynoxine B targets at HMGB1/2 to enhance autophagy forα-synuclein clearance in fly and rodent models of Parkinson's disease

Parkinson's disease(PD)is the most common neurodegenerative movement disease.It is featured by abnormal alphα-synuclein(α-syn)aggregation in dopaminergic neurons in the substantia nigra.Macroautophagy(autophagy)is an evolutionarily conserved cellular process for degradation of cellular contents,including protein aggregates,to maintain cellular homeostasis.Corynoxine B(Cory B),a natural alkaloid isolated from Uncaria rhynchophylla(Miq.)Jacks.,has been reported to promote the clearance ofα-syn in cell models by inducing autophagy.However,the molecular mechanism by which Cory B induces autophagy is not known,and theα-syn-lowering activity of Cory B has not been verified in animal models.Here,we report that Cory B enhanced the activity of Beclin 1/VPS34 complex and increased autophagy by promoting the interaction between Beclin 1 and HMGB1/2.Depletion of HMGB1/2 impaired Cory B-induced autophagy.We showed for the first time that,similar to HMGB1,HMGB2 is also required for autophagy and depletion of HMGB2 decreased autophagy levels and phosphatidylinositol 3-kinaseⅢactivity both under basal and stimulated conditions.By applying cellular thermal shift assay,surface plasmon resonance,and molecular docking,we confirmed that Cory B directly binds to HMGB1/2 near the C106 site.Furthermore,in vivo studies with a wild-typeα-syn transgenic drosophila model of PD and an A53Tα-syn transgenic mouse model of PD,Cory B enhanced autophagy,promotedα-syn clearance and improved behavioral abnormalities.Taken together,the results of this study reveal that Cory B enhances phosphatidylinositol 3-kinaseⅢactivity/autophagy by binding to HMGB1/2 and that this enhancement is neuroprotective against PD.