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Role of the caspase-8/RIPK3 axis in Alzheimer’s disease pathogenesis and Aβ-induced NLRP3 inflammasome activation
Sushanth Kumar, … , John R. Lukens, Christopher D. Deppmann
Sushanth Kumar, … , John R. Lukens, Christopher D. Deppmann
Published January 5, 2023
Citation Information: JCI Insight. 2023;8(3):e157433. https://doi.org/10.1172/jci.insight.157433.
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Research Article Inflammation Neuroscience

Role of the caspase-8/RIPK3 axis in Alzheimer’s disease pathogenesis and Aβ-induced NLRP3 inflammasome activation

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Abstract

The molecular mediators of cell death and inflammation in Alzheimer’s disease (AD) have yet to be fully elucidated. Caspase-8 is a critical regulator of several cell death and inflammatory pathways; however, its role in AD pathogenesis has not yet been examined in detail. In the absence of caspase-8, mice are embryonic lethal due to excessive receptor interacting protein kinase 3–dependent (RIPK3-dependent) necroptosis. Compound RIPK3 and caspase-8 mutants rescue embryonic lethality, which we leveraged to examine the roles of these pathways in an amyloid β–mediated (Aβ-mediated) mouse model of AD. We found that combined deletion of caspase-8 and RIPK3, but not RIPK3 alone, led to diminished Aβ deposition and microgliosis in the mouse model of AD carrying human presenilin 1 and amyloid precursor protein with 5 familial AD mutations (5xFAD). Despite its well-known role in cell death, caspase-8 did not appear to affect cell loss in the 5xFAD model. In contrast, we found that caspase-8 was a critical regulator of Aβ-driven inflammasome gene expression and IL-1β release. Interestingly, loss of RIPK3 had only a modest effect on disease progression, suggesting that inhibition of necroptosis or RIPK3-mediated cytokine pathways is not critical during midstages of Aβ amyloidosis. These findings suggest that therapeutics targeting caspase-8 may represent a novel strategy to limit Aβ amyloidosis and neuroinflammation in AD.

Authors

Sushanth Kumar, Sakar Budhathoki, Christopher B. Oliveira, August D. Kahle, O. Yipkin Calhan, John R. Lukens, Christopher D. Deppmann

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Figure 1

Induction of caspase-8 and RIPK3 expression in AD.

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Induction of caspase-8 and RIPK3 expression in AD.
(A and B) Representat...
(A and B) Representative images of the cortex, subiculum, and thalamus from 5-month-old WT and 5xFAD mice stained with Casp8 (orange) and Ripk3 (magenta) RNAscope probes. Scale bars: 40 μm. (C) Quantification of Casp8 staining. (D) Quantification of Ripk3 staining (n = 5 5xFAD mice, n = 5 WT mice). (E and F) CASP8 and RIPK3 expression data obtained from a human transcriptomic data set (GSE33000) of dorsolateral prefrontal cortex tissue from 157 patients without dementia and 310 patients with AD. (C–F) Data were analyzed by Student’s t test. Data reported as mean ± SEM (C and D) or as violin plots (E and F). Ctrl, control.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

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