Celastrol, a TFEB (transcription factor EB) agonist, is a promising drug candidate for Alzheimer disease

Abstract

Alzheimer disease (AD) is the most common neurodegenerative disease. Unfortunately, current effective therapeutics for AD are limited and thus the discovery of novel anti-AD agents is urgently needed. A key pathological hallmark of AD is the accumulation of phosphorylated MAPT/tau (microtubule associated protein tau) aggregates to form neurofibrillary tangles. Autophagy is a conserved catabolic process that degrades protein aggregates or organelles via lysosomes. TFEB (transcription factor EB), a master regulator of autophagy, transcriptionally regulates multiple autophagy, and lysosomal-related genes. A compromised autophagy-lysosomal pathway (ALP) has been implicated in AD progression, and enhancing TFEB-mediated ALP to degrade MAPT/tau aggregates is a promising anti-AD strategy. In a recent study, we showed that celastrol, a natural small molecule with an anti-obesity effect, is a novel TFEB activator, which enhances autophagy and lysosomal biogenesis both in vitro and in animal brains. Consequently, celastrol promotes the degradation of phosphorylated MAPT/tau aggregates both in cells and in the brain of P301S MAPT/tau and 3XTg mice, two commonly used AD animal models. Interestingly, celastrol also alleviates memory deficits in these mice. Altogether, celastrol enhances TFEB-mediated autophagy and lysosomal biogenesis to ameliorate MAPT/tau pathology, suggesting that celastrol represents a novel anti-AD and other tauopathies drug candidate. Abbreviations: AD: Alzheimer disease; ALP: autophagy-lysosomal pathway; MAPT/tau: microtubule-associated protein tau; MTORC1: mechanistic target of rapamycin kinase complex 1; TFEB: transcription factor EB.