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COR388, a novel gingipain inhibitor, decreases fragmentation of APOE in the central nervous system of Alzheimer’s disease patients: Human/Human trials: Other
Ist Teil von
Alzheimer's & dementia, 2020-12, Vol.16 (S9)
Erscheinungsjahr
2020
Quelle
Wiley-Blackwell Journals
Beschreibungen/Notizen
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 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.
Sprache
Englisch
Identifikatoren
ISSN: 1552-5260
eISSN: 1552-5279
DOI: 10.1002/alz.040578
Titel-ID: cdi_crossref_primary_10_1002_alz_040578
Format
–
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