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

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 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 (Aβ)-mediated mouse model of AD. We find that combined deletion of Caspase-8 and RIPK3, but not RIPK3 alone, leads to diminished Aβ deposition and microgliosis in the 5xFAD mouse model of AD. Despite its well-known role in cell death, Caspase-8 does not appear to impact cell loss in the 5xFAD model. In contrast, we found that Caspase-8 is 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 are not critical during mid stages of Aβ amyloidosis. These findings suggest that therapeutics targeting Caspase-8 may represent a novel strategy to limit Aꞵ amyloidosis and neuroinflammation in AD.

The Alzheimer's disease risk factor INPP5D restricts neuroprotective microglial responses in amyloid beta‐mediated pathology

“…However, it is important to note that we have not been able to detect appreciable levels of microglia cell death by TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) staining in the 5xFAD model in our previous studies. 27,35 Therefore, it is more likely that enhanced microglial proliferation contributes to the increase in microglia numbers seen in SHIP-1-deficeint 5xFAD mice.…”

Sex- and region-specific cortical and hippocampal whole genome transcriptome profiles from control and APP/PS1 Alzheimer’s disease mice

“…Pycard (PYD and CARD domain containing gene, encoding for adapter protein apoptosis-associated speck-like protein containing a CARD (ASC)) codes for an inflammasome component and is involved in regulation of autophagy. Previous reports demonstrated that released ASC specks can bind to Aβ, enhance its aggregation, and increase its toxicity [ 159 ]. In our study, Pycard turned out to be a unique fingerprint for the RS cortex of female APP/PS1 mice.…”

RIPK3 signaling and its role in regulated cell death and diseases

“…However, when caspase-8 was inhibited genetically or chemically, the peroxisome (RIPK3–MLKL) could bind to the NLRP3 inflammasome to promote IL-1β activation, which is consistent with other previous studies demonstrating that both pathways are intracellular in origin. These findings indicate that RIPK3-induced inflammation may be driven by factors other than necroptosis and DAMP release [ 72 , 73 ].

Fig.

…”