In:
Alzheimer's & Dementia, Wiley, Vol. 16, No. S9 ( 2020-12)
Abstract:
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 in AD CSF than non‐AD CSF. A significant decrease in LMW ApoE fragments in CSF was detected in AD subjects following 28 days of administration of COR388 compared to placebo in a Phase1b clinical study. Conclusion Our data suggest that gingipain proteases may mediate ApoE proteolysis in the brain, with higher susceptibility of ApoE4, providing a link between P. gingivalis infection and the APOE4 allele, a major risk factor in AD. Based on the literature, fragmentation of ApoE4 by gingipains would be likely to reduce synaptic maintenance and regulation of immune response as well as aggravate toxicity to cells through the generation of fragments. COR388, a small‐molecule inhibitor of lysine‐gingipain, is currently being tested in a large Phase 2/3 clinical study in subjects with mild‐to‐moderate AD.
Type of Medium:
Online Resource
ISSN:
1552-5260
,
1552-5279
Language:
English
Publisher:
Wiley
Publication Date:
2020
detail.hit.zdb_id:
2201940-6
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