Abstract
Alzheimer’s disease (AD) is a devastating neurodegenerative condition characterized by the formation of amyloid-beta (Aβ) plaques, development of neurofibrillary tangles, neuroinflammation, and neuronal loss. While it’s generally accepted that the accumulation of the protein aggregates Aβ and tau help set the stage for AD the precise molecular mediators of cell death and inflammation have yet to be fully elucidated. Identification of novel effectors that drive cell loss and inflammation would not only yield mechanistic insights, but perhaps more importantly, provide inroads into new druggable targets for disease intervention. Currently, there are two FDA-approved disease-modifying therapies for AD. Both drugs, aducanumab and lecanemab, received approval within the past two years and are monoclonal antibodies that target Aβ to facilitate its clearance from the brain parenchyma. Given their recent introductions to the therapeutic space, it remains to be seen how effective either drug will be in slowing disease progression.
In this dissertation, we set out to examine the roles of the Caspase-8 and receptor interacting protein kinase-3 (RIPK3) in AD progression. Both Caspase-8 and RIPK3 drive distinct flavors of cell death but in addition are key regulators of a number of inflammatory pathways. Moreover, the roles of either protein in AD pathogenesis have not been examined in great detail. We found that combined deletion of Caspase-8 and RIPK3, but not RIPK3 alone, led to diminished Aβ deposition and microgliosis in the 5xFAD mouse model of AD. 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. Future work will need to address the precise cell types that Caspase-8 is operating in to promote AD along with a more thorough characterization of the signaling pathways that the Caspase-8/RIPK3 axis may be influencing.
Additional experiments in this dissertation describe our preliminary work in trying to better understand the means by which microglial cells transition from homeostatic to inflamed states using single cell mass cytometry.
In summary, our findings reiterate the growing importance of developing a more comprehensive picture of the AD inflammatory state. We hope that our observations will help arm the field with more tractable therapeutic targets for AD intervention.
