biostudies-literatureKumar SNIH-NIAAlzheimer’s AssociationNIH-NINDSNIA NIH HHSUniversity of Virginia Brain InstituteNINDS NIH HHSOwens Family FoundationNIH HHSCommonwealth of Virginiae157433https://www.ebi.ac.uk/biostudies/studies/S-EPMC9977425biostudies-literatureUnknown8(3)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 precJCI insightRole of the caspase-8/RIPK3 axis in Alzheimer's disease pathogenesis and Aβ-induced NLRP3 inflammasome activation.PMC9977425Related Diseases Research Award FundNAPresidential Neuroscience Graduate FellowshipAARG-18-5661131RF1AG071996-01R01NS091617,R01NS106383R01 NS106383S10 OD025156R01 NS091617Alzheimer’sRF1 AG071996Lukens JROliveira CBKahle ADDeppmann CDBudhathoki SCalhan OYKumar SfalseRole of the caspase-8/RIPK3 axis in Alzheimer's disease pathogenesis and Aβ-induced NLRP3 inflammasome activation.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 prec2023-01-01T00:00:00Z2023 Feb2026-05-28T08:09:15.04Z2025-04-25T16:55:35.536ZS-EPMC99774253660287410.1172/jci.insight.157433