Cathepsin B Modulates Alzheimer's Disease Pathology Through SAPK/JNK Signals Following Administration of Porphyromonas gingivalis‐Derived Outer Membrane Vesicles

ABSTRACT Aim Porphyromonas gingivalis , a consensus periodontal pathogen, is thought to be involved in Alzheimer's disease (AD) progression, and P. gingivalis ‐derived outer membrane vesicles ( Pg OMVs) are a key toxic factor in inducing AD pathology. This study aimed to clarify the regulatory mechanism underlying the Pg OMV‐induced AD‐like phenotype. Materials and Methods We intraperitoneally injected Pg OMVs into the periphery of wild‐type and CatB knockout mice for 4 or 8 weeks to assess the effect of CatB on Pg OMV‐induced AD pathology. Mice were evaluated for cognitive change, tau phosphorylation, microglial activation, neuroinflammation and synapse loss. Microglial and primary neuron culture were prepared to verify the in vivo results. Results CatB deficiency significantly alleviated Pg OMV‐induced cognitive dysfunction, microglia‐mediated neuroinflammation, tau hyperphosphorylation and synapse loss. Subsequent transcriptomic analysis, immunofluorescence and immunoblotting suggested that CatB modulates microglia‐mediated neuroinflammation through stress‐activated protein kinases (SAPK)/Jun amino‐terminal kinases (JNK) signals after administration of Pg OMVs, which in turn regulates neuronal tau phosphorylation and synapse loss in a SAPK/JNK‐dependent manner. Conclusion Our study unveils a previously unknown role of CatB in regulating Pg OMV‐induced AD pathology.