Microglial serine racemase knockout alleviates Alzheimer-like neuropathology and behavioral deficit via lactylation-mediated anti-inflammation.

Serine racemase (SR) dysregulation associates with brain aging and Alzheimer's disease (AD), as both a deficiency and an excess of D-serine can impact synaptic neurotransmission and the integrity of synapses. Neuronal SR decreases with aging, while glial SR is upregulated in AD. However, the role of SR in microglia involved in AD remains elusive. Here, Srr knockdown/knockout in microglia enhanced whereas overexpression of SR inhibited phagocytosis. Lipopolysaccharide-treated Srr(-/-) microglia upregulated anti-inflammatory factors-an effect blocked by histone lactylation inhibition. Conditional microglial Srr knockout (5×FAD;Lyz2(cre);Srr(fl/fl)) improved spatial memory and reduced amyloid plaques (male-specific) in 5×FAD mice, with elevated lactylation of histone H3 lysine 18 (H3K18la), pyruvate kinase M2, and arginase1 in plaque-associated microglia. Cerebral D-amino acid oxidase and microglial SR and H3K18la were more prominent in males. Collectively, microglia-specific Srr deletion reprograms microglia toward an anti-inflammatory phenotype and enhanced phagocytic capacity partialy mediated by histone lactylation, thereby mitigating AD neuropathology and improving cognitive function-where sex-specific modulation of D-serine contributes to these beneficial effects. Overall, this study delineates the functional roles of microglial SR in phagocytosis, inflammatory responses, and learning-memory behaviors in AD-related models, thereby implicating microglial SR as a potential therapeutic target for AD.