| First Author | Kumar S | Year | 2023 |
| Journal | JCI Insight | Volume | 8 |
| Issue | 3 | PubMed ID | 36602874 |
| Mgi Jnum | J:352428 | Mgi Id | MGI:7441376 |
| Doi | 10.1172/jci.insight.157433 | Citation | Kumar S, et al. (2023) Role of the caspase-8/RIPK3 axis in Alzheimer's disease pathogenesis and Abeta-induced NLRP3 inflammasome activation. JCI Insight 8(3) |
| abstractText | 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 (Abeta-mediated) mouse model of AD. We found that combined deletion of caspase-8 and RIPK3, but not RIPK3 alone, led to diminished Abeta 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 Abeta-driven inflammasome gene expression and IL-1beta 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 Abeta amyloidosis. These findings suggest that therapeutics targeting caspase-8 may represent a novel strategy to limit Abeta amyloidosis and neuroinflammation in AD. |
