Inflammasome-based Alzheimer's disease therapy in the context of diabetes

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Scope of Work / Abstract This Administrative Supplement proposal is to investigate the role of inflammasome signaling in models of Alzheimer's disease (AD) complicated by diabetes mellitus (DM). AD is a progressive neurodegeneration accounting for 60-70% of all the dementia worldwide. DM, the metabolic syndrome responsible for a variety of complications including diabetic retinopathy (the subject of the parent proposal), is characterized by hyperglycemia, hyperinsulinemia, and insulin resistance. Numerous epidemiologic analyses have identified DM as a significant risk factor and comorbidity for AD. In addition, DM and AD share inflammasome activation as pathomechanisms, and each entity has independently been shown to be responsive to inflammasome inhibition. We propose to test the overall hypothesis that inflammasome inhibition reduces neuroinflammation and improves cognitive outcomes in mouse AD models that are complicated by the co-morbidity of DM. To accomplish this, we will critically assess the spatial and temporal kinetics of inflammasome activation in the brain in combined DM/AD models. In addition, we will test whether the presence of DM affects the efficacy of inflammasome inhibition on cognitive outcomes of AD mouse models. As such, this supplement request focused on AD is within the scope of the active parent NIH award and has the potential to stimulate new studies for examining novel molecular and biochemical mechanisms of inflammasome activation in AD in the presence of metabolic disorders. We predict that establishing inflammasome as a key link between DM and AD will stimulate additional activity on the part of endocrinologists, immunologists, and neurobiologists thereby leading to progress in deciphering and potentially treating AD and related dementias complicated by DM. This supplement will also enable our laboratory to develop a focus on AD and related dementias by generating additional experimental data that can be leveraged to submit new proposals focused directly on AD and related dementias.