NVP-BEZ235 enhances autophagy and ameliorates cognitive deficits by targeting tauopathies

Abstract

Tauopathies are a class of neurodegenerative disorders characterized by the abnormal accumulation of hyperphosphorylated tau (p-tau) and the formation of neurofibrillary tangles. Autophagy, a fundamental cellular degradation pathway, plays a pivotal role in maintaining proteostasis by facilitating the clearance of misfolded and aggregated proteins. In tauopathies, however, autophagic processes are often impaired, contributing to the pathological buildup of p-tau. NVP-BEZ235, a dual inhibitor of the mammalian target of rapamycin (mTOR) and PI3K, has previously been evaluated in phase I clinical trials for solid tumors and lymphomas. In this study, we investigated the therapeutic potential of NVP-BEZ235 in tauopathy models, both in vitro and in vivo. In SH-SY5Y cells stably expressing human P301L-mutant tau (SH-Tau), NVP-BEZ235 treatment induced a time-dependent increase in LC3B-II and a decrease in p62 levels, consistent with enhanced autophagic activity. Autophagic flux analysis further confirmed the promotion of autophagy upon mTOR pathway inhibition. NVP-BEZ235 significantly reduced tau phosphorylation at multiple residues, including Ser262, Ser396, Ser404, and Thr231, without eliciting cytotoxic effects. In a transgenic mouse model of tauopathy (P301S), chronic treatment with NVP-BEZ235 (20 mg/kg/day for two months) resulted in a marked reduction of both RIPA-soluble and -insoluble p-tau species in the brain. Spatial learning and memory, assessed through Morris water maze and novel object recognition tests, were significantly improved in treated mice. Furthermore, NVP-BEZ235 administration reduced neuroinflammatory markers and pro-inflammatory cytokine levels (TNF-α, IL-1β, IL-6), while also enhancing autophagic markers in brain tissue. Hematological analysis and organ histology revealed no signs of systemic toxicity. Collectively, these findings demonstrate that NVP-BEZ235 facilitates tau clearance by enhancing autophagy through mTOR inhibition, thereby mitigating cognitive deficits and neuroinflammation in tauopathy models. This study supports the therapeutic potential of NVP-BEZ235 as a promising candidate for the treatment of tau-related neurodegenerative diseases.