Porphyromonas gingivalis disrupts hippocampal circadian clock via PI3K/AKT pathway, exacerbating Alzheimer‐like pathology

Jun 10, 2026Alzheimer's & dementia : the journal of the Alzheimer's Association

Porphyromonas gingivalis may disrupt the brain’s daily rhythm through the PI3K/AKT pathway, worsening Alzheimer-like damage

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Abstract

Oral infection with P. gingivalis for 6 months reduced the rhythmic activity of the Bmal1 gene in the hippocampus.

Dampened Bmal1 rhythms were observed in the hippocampus following infection with P. gingivalis.
Decreased levels of phosphorylated protein kinase B (p-AKT) were noted alongside increased activation of glial cells.
Elevated amyloid beta (Aβ) and interleukin 1β (IL-1β) were associated with P. gingivalis-induced periodontitis.
In glial cells, P. gingivalis disrupted Bmal1 oscillation, and inhibition of PI3K mimicked these disruptions.
Restoration of AKT signaling was linked to the recovery of rhythmic Bmal1 activity and reduced glial activation.

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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.