Visual system and cognitive biology in normal animals versus in an animal model of Alzheimer's disease with or without diabetes treated with solo or dual inflammasome inhibitors

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ABSTRACT Alzheimer’s disease (AD) is a progressive neurodegeneration that accounts for the majority of dementia worldwide. In addition to cognitive deficits, visual dysfunction is also common in AD and may be due to pathology in the retina. Diabetes mellitus (DM), the metabolic syndrome responsible for diabetic retinopathy, is characterized by hyperglycemia, hyperinsulinemia, and insulin resistance. DM has been identified as a significant risk factor and comorbidity for AD in epidemiological studies and clinical trials. We recently identified a novel dual NLRP3-NLRC4 inflammasome that may contribute to neurologic pathology. In this study, we will achieve complementary goals of evaluating the consequences of AD complicated by DM on cognition, vision, and molecular pathological hallmarks. In addition, using preclinical small molecule inhibitors, we will determine the efficacy of dual NLRP3-NLRC4 inflammasome inhibition on visual and cognitive readouts in AD models in the presence or absence of bona fide DM. We propose to address this gap by testing solo and dual inflammasome inhibitors in models of combined DM/AD. We hypothesize that dual inflammasome inhibition is superior to solo inflammasome inhibition in preventing visual dysfunction and cognitive impairment in DM/AD mice. Together these studies will elucidate whether combined DM/AD exacerbates retinal and brain pathologies, and identify a potential therapeutic strategy to address these complex and prevalent conditions.