Gingipains Identified in Alzheimer's Disease Brains Differentially Fragment ApoE Proteins

Gingipains are protease virulence factors from the periodontal bacterial pathogen Porphyromonas gingivalis and were recently identified in greater than 90% of Alzheimer’s disease (AD) brains. Studies in wild-type mice and rats have demonstrated that P. gingivalis invades the brain after oral infection and triggers characteristic AD pathology. The APOE4 gene is the greatest genetic risk factor for sporadic AD, and ApoE protein fragments have been identified in the brain and cerebrospinal fluid of AD patients, but the protease(s) responsible for ApoE fragmentation remain unknown. Here we report that gingipains directly cleave ApoE proteins in vitro, with ApoE4 preferentially cleaved compared to ApoE3 and ApoE2. Cerebrospinal fluid analyzed from a 28-day phase 1b clinical trial of atuzaginstat, a brain-penetrant gingipain inhibitor, in mild-to-moderate AD patients revealed a significant reduction of low-molecular-weight ApoE fragments compared to placebo that was strongly correlated with a reduction in the pathologic decline of CSF Aβ 1-42 levels.