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This study was conducted to investigate the prevalence of P. gingivalis in the AD brain and to elucidate possible P. gingivalis–dependent mechanisms of action for neurodegeneration and AD pathology. In addition, we performed a series of preclinical studies to enable the development of a therapeutic compound against P. gingivalis–induced AD. To demonstrate the presence of gingipain antigens in the AD brain, TMAs containing nondemented control and AD brain tissue were used for IHC. To avoid potential bias and subjective elements in assessing the results, stained TMAs were scanned and images were analyzed for gingipain IR using the MetaMorph image analysis program. Evidence for the presence of P. gingivalis in the AD brain was further verified by IP, WB, and PCR. To demonstrate the presence of P. gingivalis in the CNS of living patients prospectively diagnosed with probable AD, CSF was analyzed for P. gingivalis by PCR. The in vitro experiments to demonstrate P. gingivalis fragmentation of tau analyzed by WB and MS were designed after detecting the correlation of increased tau load with gingipains in the TMAs and the colocalization of gingipain with tau tangles in human AD brain. To study the efficacy of gingipain inhibitors and neurodegenerative effects of chronic P. gingivalis infection in vivo, we developed a mouse model for chronic infection with P. gingivalis. The sample size for the mouse model for brain infection with P. gingivalis was empirically determined on the basis of effect size and SD. A blinded observer performed quantification of the loss of hippocampal GABAergic neurons after P. gingivalis brain infection and the number of degenerating neurons after intrahippocampal injection of gingipains. The efficacy of the top lead compound, COR388, was determined in the brain by qPCR for P. gingivalis–specific genes and by enzyme-linked immunosorbent assay (ELISA) for Aβ1–42 and TNFα. Animals were assigned to each experimental group with an equal probability of receiving vehicle or treatment.

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