COR388, a novel gingipain inhibitor, decreases fragmentation of APOE in the central nervous system of Alzheimer’s disease patients

作者：Debasish Raha, Sean Broce, Ursula Haditsch, Leo Rodriguez, Florian Ermini, Mike Detke, Shirin Kapur, D. David Hennings, Theresa Roth, Mai K. Nguyen, Leslie J. Holsinger, Casey Lynch, Steve Dominy · 发表于：Alzheimer s & Dementia · 年份：2020 · DOI：10.1002/alz.040578 · 被引用次数：11 · 研究领域：Oral and gingival health research、Alzheimer's disease research and treatments、Oral microbiology and periodontitis research

Abstract Background We identified the bacterial pathogen, Porphyromonas gingivalis (Pg), and its protease virulence factors, gingipains, in the brain of patients with Alzheimer’s disease (AD). Gingipain levels in AD brains were shown to significantly correlate with AD diagnosis and tau and ubiquitin pathology. The neurodegeneration and AD‐like pathology in Pg infected mice were blocked after oral administration of COR388, an orally bioavailable, brain penetrant small‐molecule that irreversibly inhibits lysine‐gingipain. Since ApoE4 is the greatest genetic risk factor for sporadic AD, we investigated if ApoE proteins are targets of gingipain proteolysis. Method In vitro proteolysis of recombinant ApoE proteins , Mass Spectrometry (MS) analysis of gingipain cleavage sites , and detection of ApoE proteolytic fragments in brain and CSF. Result ApoE proteins were cleaved by gingipains rapidly, and ApoE4 was a preferred substrate over ApoE3. Gingipain inhibitors blocked ApoE proteolysis. MS analysis confirmed higher susceptibility of ApoE4 to gingipain cleavage. MS analysis enabled the identification of cleavage sites and the majority of these sites were concentrated near the carboxy‐terminal of the protein. MS analysis performed on low‐molecular‐weight (LMW) fragments of ApoE4 from a human AD brain, homozygous for the APOE4 allele, identified peptide fragments from this same region. Western blot analysis of AD CSF revealed a higher level of LMW ApoE proteolytic cleavage products i...