Role of inflammasomes in Alzheimer's Disease

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PROJECT ABSTRACT Supplement to R01 AG059752-03: Neuroinflammation is an important component of Alzheimer's disease (AD) and Fronto-temporal dementia (FTD). However, the molecular mechanism by which inflammation modulates AD and FTD progression are not defined. We discovered that both AD and FTD patients uniformly have evidence of activated inflammasomes in their brains. We have also found that systemic inflammation promotes AD disease and increases the deposition of Ab plaques, in part by reducing microglial clearance of Aβ in the brain. This process was dependent on inflammasomes, as NLRP3 KO mice showed clear protection with nearly normalized microglial morphology and Aβ clearance. We have also noted that NLRP3 inflammasome activation drives tau pathology by inducing tau hyper-phosphorylation. Taken together, these observations suggest that systemic inflammation likely contributes to neurologic diseases, particularly AD and FTD, by promoting the accumulation of Ab plaques and inducing the phosphorylation and aggregation of tau in neurofibrillary tangles. Acute COVID-19 is associated with a hyper-inflammatory cytokine storm and more than a third of patients develop neurologic symptoms. We believe that acute COVID-19 driven inflammation will aggravate pre- existing neurologic disorders, such as Alzheimer’s Disease (AD) and fronto-temporal dementia (FTD) via activation NLRP3 inflammasomes and downstream inflammasome-dependent cytokines in the brain. Successful completion of this supplemental Aims will elucidate the role of inflammasome-generated cytokines in COVID-19 associated neurologic symptoms and could result in novel translational approaches designed to specifically halt the inflammation that drives neuroinflammation in this disease. We also hypothesize that COVID-19 inflammation can potentially accelerate cognitive decline in AD and FTD patients. This study has the potential to identify therapeutic targets to prevent the neurologic disorders that occur in many COVID-19 hospitalized patients and to determine the impact of COVID-19 inflammation on AD and FTD pathology and disease progression.