Chunmei Huang, Qin Cai, Zeru Feng, Zhang Chenze, Zhiqiang Luo, Xingqun Cheng, H Wu
INTRODUCTION: Periodontal pathogen Porphyromonas gingivalis is epidemiologically linked to Alzheimer's disease (AD), yet how oral infection disrupts the central circadian clock to drive hippocampal neurodegeneration remains unknown. METHODS: C57BL/6 mice received oral P. gingivalis for 6 months; hippocampal clock gene oscillations, phosphorylated protein kinase B (p-AKT), glial fibrillary acidic protein (GFAP)/Ionized calcium-binding adapter molecule 1 (Iba1), and amyloid beta (Aβ) load were quantified. C8-D1A astrocytes and BV2 microglia were infected with P. gingivalis ± phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT inhibitor or agonist; Bmal1 (brain and muscle ARNT-like 1)/Clock (circadian locomotor output cycles kaput) were knocked down by lentivirus. RESULTS: P. gingivalis-induced periodontitis dampened hippocampal Bmal1 rhythms, lowered p-AKT, activated glia, and elevated Aβ and interleukin 1β (IL-1β). In glial cells, P. gingivalis flattened Bmal1 oscillation; PI3K blockade mimicked these effects, whereas AKT agonist restored rhythms and suppressed GFAP/Iba1/IL-1β. Bmal1 knockdown alone triggered glial activation and cytokine release. DISCUSSION: P. gingivalis oral infection suppresses PI3K/AKT signaling, destabilizing glial circadian clocks and unleashing neuroinflammation that fosters hippocampal AD-like pathology; rescuing PI3K/AKT or clock function may mitigate the oral-brain axis in AD.