Puerarin alleviates memory deficits through the modulation of D‑serine-mediated N-methyl-D-aspartate receptor activity in presenilin 1/2 conditional double knockout mice

Background Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline, the formation of amyloid-β plaques and neurofibrillary tangles, and synaptic dysfunction. Puerarin (PUE), an isoflavone C-glycoside extracted from Pueraria lobata , has demonstrated potential in attenuating AD-related cognitive decline; however, the mechanisms governing the effects of PUE remain incompletely understood. Purpose To investigate the mechanisms underlying PUE’s anti-AD effects. Methods Presenilin 1/2 conditional double knockout mice served as the AD model. Following one month of PUE administration, memory function was evaluated through behavioral testing, and hippocampal synaptic plasticity was assessed using electrophysiological recordings. D‑serine levels were quantified via ELISA. Additionally, Western blotting and qRT-PCR were employed to analyze the expression of glutamate receptor subunits and key enzymes involved in D‑serine metabolism. The mechanistic role of D‑serine was further validated through intrahippocampal D‑serine injections in mice and the application of a serine racemase (SR) inhibitor in N2a cells. Results PUE administration reversed memory impairment and enhanced both hippocampal long-term potentiation and synaptic transmission by increasing the open probability of N-methyl-D-aspartate receptor (NMDAR) channels. Furthermore, PUE elevated D‑serine levels and upregulated the expression of SR. Notably, these therapeutic effects were replicated by exogenous D‑serine and abolished by treatment with an SR inhibitor. Conclusion These findings indicate that PUE alleviates cognitive deficits by promoting SR-mediated D‑serine biosynthesis and subsequently restoring NMDAR activity. Accordingly, PUE represents a viable therapeutic candidate for the prevention and management of AD.