Microglial metabolic reprogramming drives the therapeutic effects of bavachinin on brain network function and memory...

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-β (Aβ) plaques and pervasive cognitive decline. Bavachinin, a natural flavonoid derived from the traditional medicinal herb Psoralea corylifolia, has previously been demonstrated to inhibit Aβ aggregation in vitro. However, its potential to alleviate cognitive impairment, restore large-scale brain network dysfunctions, and mitigate AD-related pathology in vivo remains elusive.

In this study, we systematically evaluated the therapeutic efficacy of bavachinin on AD-associated pathology, cortical slow-wave activity (SWA), and behavioral phenotypes in 5xFAD transgenic mice. We utilized behavioral assessments to evaluate learning and memory, mesoscopic wide-field calcium imaging to assess cortical network dynamics, and histological analyses to measure cerebral Aβ deposition. Furthermore, pharmacological inhibition was employed to investigate the mechanistic role of mitochondrial oxidative phosphorylation (OXPHOS).

Behavioral assessments revealed that bavachinin administration significantly rescued deficits in learning and memory. Mesoscopic wide-field calcium imaging further demonstrated that bavachinin substantially enhanced the synchrony of cortical SWA while reducing its frequency in 5xFAD mice, indicating a restoration of network-level dynamics. Histological analyses confirmed a marked reduction in cerebral Aβ deposition, which occurred independent of Aβ production pathways. Mechanistically, bavachinin bolstered microglial Aβ phagocytosis and chemotactic migration by promoting mitochondrial OXPHOS, thereby revitalizing cellular energy metabolism. Notably, pharmacological inhibition of OXPHOS partially abrogated the therapeutic benefits of bavachinin, suggesting that the augmentation of mitochondrial function is a requisite for its anti-AD effects.

In summary, bavachinin alleviates cognitive impairment and neuropathology in AD model mice by driving microglial metabolic reprogramming and facilitating Aβ clearance. These findings highlight its robust potential as a therapeutic candidate for AD.