Fruit-Derived Citri Reticulatae Semen Extract Attenuates Alzheimer's Disease Neuroinflammation and Cognitive Impairment via Modulation of the PI3K/Akt/FoxO1 Pathway.

Bioactive compounds from edible plants represent a promising multi-target approach for mitigating Alzheimer's disease (AD), in which neuroinflammation is a key pathological driver. Building on previous evidence that Citri Reticulatae Semen extract (CRSE) exerts neuroprotective effects, this study investigated its impact on AD related neuroinflammation and the underlying mechanisms. The major constituents of CRSE were profiled by HPLC-MS. CRSE efficacy was evaluated in Aβ1-42 stimulated BV-2 microglia, 3×Tg-AD mice, and Tg (apoeb: lynEGFP) zebrafish larvae. We found that CRSE significantly suppressed Aβ-induced microglial activation, NLRP3 inflammasome signaling, and pro-inflammatory cytokine release in BV-2 cells. In 3×Tg-AD mice, CRSE supplementation improved spatial learning and memory, reduced hippocampal glial reactivity and neuronal loss, and attenuated tau pathology and NLRP3/ASC/Caspase-1 activation. It also reduced microglial activation in zebrafish. Integrated transcriptomics and network pharmacology analyses converged on the PI3K/Akt/FoxO1 axis. Subsequent validation demonstrated that CRSE restored Aβ-impaired phosphorylation of PI3K, Akt, and FoxO1, and its anti-inflammatory effects were attenuated by the PI3K inhibitor. Collectively, these findings demonstrate that the fruit-derived CRSE ameliorates AD-related pathology by modulating the PI3K/Akt/FoxO1 pathway and suppressing NLRP3 inflammasome activation. This study provides a mechanistic basis for considering CRSE as a botanical candidate for dietary interventions aimed at neuroprotection in AD.