CRP Deficiency Rescues Periodontitis‐Induced Hippocampal Neurogenesis Impairment by Suppressing OPC‐Derived BMP4 Signaling in Rats

ABSTRACT Chronic periodontitis (PD) is an emerging risk factor for mental disorders, although the underlying mechanisms remain unclear. Here, we show that silk ligature‐induced PD in rats leads to anxiety/depression‐like behaviors and impaired hippocampal neurogenesis. These alterations were associated with elevated hippocampal levels of C‐reactive protein (CRP), derived predominantly from the periphery. Knockout of Crp attenuated these PD‐induced hippocampal impairments, largely through downregulation of bone morphogenetic protein 4 ( Bmp4 ). Single‐nucleus RNA sequencing (snRNA‐seq) analysis revealed that hippocampal Bmp4 expression is predominantly expressed by oligodendrocyte precursor cells (OPCs). Subsequent analyses associated CRP deficiency with enhanced functional resilience of OPCs. Critically, inhibition of the CRP‐BMP4 axis restored the neuronal differentiation suppressed by PD and alleviated the associated behavioral abnormalities. These findings elucidate a novel pathway linking periodontal disease to central nervous system disorders and suggest the CRP‐BMP4 axis as a potential therapeutic target for preventing PD‐related neurological complications.