Pterostilbene targets microglia-mediated neuroinflammation for Alzheimer's therapy.

Microglia-mediated neuroinflammation is a key driver of Alzheimer's disease (AD) progression, exacerbating neuronal damage and pathological changes. Pterostilbene (PTE), a natural anti-inflammatory stilbenoid, shows neuroprotective potential in AD, but its specific mechanism in regulating AD-related neuroinflammation remains unclear. Here, we explored the anti-neuroinflammatory effect and mechanisms of PTE against AD. APPswe/PS1dE9 (APP/PS1) transgenic mice were treated intragastrically with PTE for 4 weeks, followed by evaluation of cognitive function and pathological changes. Amyloid-β burden, Tau protein phosphorylation, microglial activation, and proinflammatory cytokines production were analyzed. To further investigate the potential mechanism of PTE, an integrated approach combining network pharmacology, RNA sequencing, molecular docking, molecular dynamics simulations, and cell transfection techniques were conducted. Our results showed that PTE treatment improved cognitive impairment, amyloid-β deposits, Tau protein phosphorylation, microglia activation, and production of tumor necrosis factor-α, interleukin-1β, and interleukin-6 in vivo and in vitro. Notably, molecular docking predicted that PTE has binding affinity for Janus kinase 2 (JAK2) at LYS-857, LYS-882, and LEU-932. Consistently, site-directed mutagenesis reduced the inhibitory effect of PTE on JAK2/signal transducer and activator of transcription 3 (STAT3) phosphorylation, supporting JAK2 as a functional target. Meanwhile, we revealed that PTE effectively inhibited activation of microglia in the APP/PS1 mice by regulating JAK2-STAT3 pathway. These findings indicate that PTE treatment could attenuate microglia-mediated neuroinflammation via regulating JAK2-STAT3 signaling pathway, which might provide a novel option to elucidate the effects of PTE on AD.