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

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.

C‐reactive protein; bone morphogenetic protein 4; hippocampus; oligodendrocyte progenitor cells; periodontal disease.