Role of inflammasomes in Alzheimer's Disease

PROJECT ABSTRACTSupplement 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 notdefined. We discovered that both AD and FTD patients uniformly have evidence of activated inflammasomes intheir brains. We have also found that systemic inflammation promotes AD disease and increases thedeposition of Ab plaques, in part by reducing microglial clearance of Aβ in the brain. This process wasdependent on inflammasomes, as NLRP3 KO mice showed clear protection with nearly normalized microglialmorphology and Aβ clearance. We have also noted that NLRP3 inflammasome activation drives tau pathologyby inducing tau hyper-phosphorylation. Taken together, these observations suggest that systemicinflammation likely contributes to neurologic diseases, particularly AD and FTD, by promoting the accumulationof 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 patientsdevelop 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) viaactivation NLRP3 inflammasomes and downstream inflammasome-dependent cytokines in the brain.Successful completion of this supplemental Aims will elucidate the role of inflammasome-generated cytokinesin COVID-19 associated neurologic symptoms and could result in novel translational approaches designed tospecifically halt the inflammation that drives neuroinflammation in this disease. We also hypothesize thatCOVID-19 inflammation can potentially accelerate cognitive decline in AD and FTD patients. This study hasthe potential to identify therapeutic targets to prevent the neurologic disorders that occur in many COVID-19hospitalized patients and to determine the impact of COVID-19 inflammation on AD and FTD pathology anddisease progression.