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

34 Pages Posted: 3 May 2021 Publication Status: Review Complete

See all articles by Debasish Raha

Debasish Raha

Cortexyme, Inc.

Sean Broce

Cortexyme, Inc.

Shirin Arastu-Kapur

Cortexyme, Inc.

Ursula Haditsch

Cortexyme, Inc.

Mai Nguyen

Cortexyme, Inc.

Leo Rodriguez

Cortexyme, Inc.

Florian Ermini

Cortexyme, Inc.

Jianhong Wang

Cortexyme, Inc.

D. David Hennings

Cortexyme, Inc.

Michael J. Detke

Cortexyme, Inc.

Casey Lynch

Cortexyme, Inc.

Leslie J. Holsinger

Cortexyme, Inc.

Stephen Dominy

Cortexyme, Inc.

More...

Abstract

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.

Keywords: Alzheimer’s disease, Porphyromonas gingivalis, gingipains, ApoE4

Suggested Citation

Raha, Debasish and Broce, Sean and Arastu-Kapur, Shirin and Haditsch, Ursula and Nguyen, Mai and Rodriguez, Leo and Ermini, Florian and Wang, Jianhong and Hennings, D. David and Detke, Michael J. and Lynch, Casey and Holsinger, Leslie J. and Dominy, Stephen, Gingipains Identified in Alzheimer's Disease Brains Differentially Fragment ApoE Proteins. Available at SSRN: https://ssrn.com/abstract=3838996 or http://dx.doi.org/10.2139/ssrn.3838996
This version of the paper has not been formally peer reviewed.

Debasish Raha

Cortexyme, Inc. ( email )

269 East Grand Ave.
South San Francisco, CA
United States

Sean Broce

Cortexyme, Inc. ( email )

269 East Grand Ave.
South San Francisco, CA
United States

Shirin Arastu-Kapur

Cortexyme, Inc. ( email )

269 East Grand Ave.
South San Francisco, CA
United States

Ursula Haditsch

Cortexyme, Inc. ( email )

269 East Grand Ave.
South San Francisco, CA
United States

Mai Nguyen

Cortexyme, Inc.

269 East Grand Ave.
South San Francisco, CA
United States

Leo Rodriguez

Cortexyme, Inc.

269 East Grand Ave.
South San Francisco, CA
United States

Florian Ermini

Cortexyme, Inc. ( email )

269 East Grand Ave.
South San Francisco, CA
United States

Jianhong Wang

Cortexyme, Inc.

269 East Grand Ave.
South San Francisco, CA
United States

D. David Hennings

Cortexyme, Inc. ( email )

269 East Grand Ave.
South San Francisco, CA
United States

Michael J. Detke

Cortexyme, Inc. ( email )

269 East Grand Ave.
South San Francisco, CA
United States

Casey Lynch

Cortexyme, Inc.

269 East Grand Ave.
South San Francisco, CA
United States

Leslie J. Holsinger

Cortexyme, Inc. ( email )

269 East Grand Ave.
South San Francisco, CA
United States

Stephen Dominy (Contact Author)

Cortexyme, Inc. ( email )

269 East Grand Ave.
South San Francisco, CA
United States

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