Total glucosides of paeony ameliorate cognitive impairment by promoting ketogenesis and modulating Glu-AMPAR signaling.

Impaired cerebral energy metabolism and synaptic dysfunction are closely associated with cognitive decline in Alzheimer's disease (AD). Although total glucosides of paeony (TGP) have demonstrated neuroprotective properties, whether TGP protects synaptic function through regulation of cerebral energy metabolism remains unclear. To investigate the neuroprotective mechanisms of TGP, we established D-galactose-induced aging mice model and an insulin-resistant SH-SY5Y cell model and combined behavioral tests, histological analyses, biochemical assays, transcriptomics, and molecular biology approaches. TGP ameliorated cognitive deficits and hippocampal synaptic damage in D-galactose mice. These beneficial effects were associated with restoration of cerebral energy metabolism through enhanced ketogenesis and ketone utilization, accompanied by improved mitochondrial function and reduced oxidative stress, neuroinflammation, and Aβ accumulation. To further investigate the underlying mechanisms, Transcriptomic analysis revealed alterations in neurotransmitter- and synapse-related pathways. In vivo studies demonstrated that TGP maintained synaptic homeostasis by modulating Glu-AMPAR signaling, restoring the Glu-Gln cycle, correcting AMPAR subunit imbalance, and suppressing CaMKIIα overactivation. Furthermore, in vitro experiments confirmed that TGP inhibited neuronal apoptosis through AMPAR-related signaling pathways. Collectively, these findings suggest that TGP may protect against AD-related cognitive impairment by restoring cerebral energy metabolism and regulating Glu-AMPAR signaling to maintain synaptic homeostasis, providing new insights into the neuroprotective mechanisms of TGP.