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
Figure 6
Caspase-8 promotes Aβ-induced IL-1β release from mixed astrocyte–microglia cultures.
