Porphyromonas gingivalis (Pg), a keystone pathogen in chronic periodontitis, has been identified as an emerging risk factor for Alzheimer’s disease (AD). Pg can promote the accumulation of amyloid β protein (Aβ), a characteristic feature of AD pathology. However, the underlying mechanism, particularly in Aβ clearance, remains poorly understood. Here, by using 3 different strains of Pg, ATCC33277, W50, and W83, we discovered that APP/PS1 mice infected with all 3 Pg strains showed decreased microglial Aβ internalization, increased Aβ deposition in the brain, and impaired cognitive function. Using in vitro experiments, we further demonstrated that all 3 Pg strains inhibited microglial Aβ clearance, where gingipains, a group of toxic proteases derived from Pg, were involved. Gingipains were shown to hydrolyze CD14, subsequently impeding the CD14-mediated Vav-Rac/Cdc42 signaling cascade, which ultimately suppressed phagocytosis. Gingipain inhibitor could effectively restore microglial Aβ clearance and diminish Aβ deposition, leading to improved cognitive function in Pg-infected APP/PS1 mice. These findings may provide new insights into the mechanism through which Pg impairs microglial Aβ clearance to aggravate AD phenotypes, suggesting that gingipain inhibitors could be potential therapeutics for treating Pg-associated AD.
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