Triptolide alleviates cognitive impairment via autophagy and Akt/mTOR/p70S6K pathway in an APP/PS1 Alzheimer’s disease mouse model

Alzheimer's Disease (AD) is characterized by cognitive decline and synaptic dysfunction, with amyloid-beta (Aβ) accumulation contributing significantly to disease pathology. This study aimed to investigate the therapeutic potential of Triptolide (TP), a compound known for its anti-inflammatory and neuroprotective properties, in an APP/PS1 transgenic mouse model of AD. We evaluated TP's efficacy in mitigating cognitive impairments, its effects on synaptic plasticity, Aβ peptide levels, and the modulation of autophagy and the Akt/mTOR/p70S6K signaling pathway.The Morris Water Maze (MWM) test assessed cognitive function, where TP treatment significantly decreased escape latencies in AD mice without affecting swimming speeds, suggesting improved spatial learning and memory independent of motor function. Synaptic plasticity was evaluated through Long-term Potentiation (LTP) and depotentiation (DEP) in the hippocampal perforant path-dentate gyrus (PP-DG) pathway. Our results demonstrated enhanced LTP and reduced DEP in TP-treated AD mice, reflecting improved synaptic health.Further, TP administration resulted in upregulation of synaptic proteins PSD95 and SYP, and preservation of neuronal integrity. Notably, TP treatment led to a reduction in hippocampal Aβ1-40 level, suggesting a decrease in Aβ neuropathology. At the molecular level, TP normalized autophagic activity, evidenced by reduced LC3 II/ LC3 I ratios and Beclin-1 expression. Additionally, TP reactivated the Akt/mTOR/p70S6K pathway, as shown by increased phosphorylation of these proteinsConclusively, our study presents TP as a promising therapeutic agent that can reverse cognitive deficits and correct synaptic and molecular dysfunctions in AD. The findings suggest that TP's benefits are mediated through the modulation of autophagy and the Akt/mTOR/p70S6K pathway, providing a foundation for future therapeutic strategies against AD.