Role of the caspase-8/RIPK3 axis in Alzheimer's disease pathogenesis and A beta-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 beta-mediated (A beta mediated) mouse model of AD. We found that combined deletion of caspase-8 and RIPK3, but not RIPK3 alone, led to diminished A beta 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 A beta-driven inflammasome gene expression and IL-1 beta 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 A beta amyloidosis. These findings suggest that therapeutics targeting caspase-8 may represent a novel strategy to limit A beta amyloidosis and neuroinflammation in AD.