Caveolin-1–Mediated Blood-brain Barrier Transcytosis Promotes Porphyromonas gingivalis Invasion and Alzheimer’s Disease-Like Changes

Pathogens such as Porphyromonas gingivalis ( P. gingivalis ) may lead to Alzheimer’s disease (AD), but how they get into the brain and cause AD remains unclear, especially their level in blood is usually low. AD involves early breakdown of the blood-brain barrier (BBB). BBB disruption may allow blood-derived neurotoxic components to penetrate the BBB and enter the brain. We investigated whether BBB disruption permits P. gingivalis to enter the brain and accelerate disease-related changes. Using animal models, human BBB organoids and bEnd.3 cells, we found that a leaky BBB, especially through increased caveolin-1-dependent transcytosis, allowed P. gingivalis to cross into the brain. The bacteria triggered the hyperphosphorylation of Tau protein, increased Aβ levels, and sustained neuroinflammation via activated glial cells. These findings indicate that BBB dysfunction facilitates P. gingivalis invasion, creating a vicious cycle of infection and neurodegeneration that may drive AD progression.