Mechanisms of Alzheimers disease pathogenesis in SARS CoV2 infection

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PROJECT SUMMARY This application is a supplement request to our P51 base grant to Tulane National Primate Research Center (TNPRC) to further the investigation of the Post-Acute Sequelae of SARS-CoV-2 infection (PASC). This application investigates the overarching hypothesis that SARS-CoV-2-induced dysregulation of metabolic pathways involved in tryptophan metabolism and upregulation of DNER, a potential marker of ongoing neurodegeneration, contributes to Alzheimer’s disease (AD) progression. We hypothesize that these alterations contribute to major pathogenic features of CoVID-19 infection and PASC, particularly neurocognitive disturbances, which have increased prevalence in persons previously infected with SARS-CoV-2. Alterations in the Kyn/Tryp levels are known to accelerate AD. Our published studies have shown that systemic Kyn/Typ levels correlate with the severity of lung pathology in the NHP model of SARS-CoV-2 infection. Our in-vitro studies demonstrate that spike enhances amyloid beta aggregation and neurotoxicity in hippocampal neurons. The studies proposed in Aim 1 will utilize samples from ongoing studies on PASC in African Green monkeys (AGMs). Aim 2 studies will be performed in 5XFAD mice, a well-established AD model, to assess the impact of SARS- CoV-2 Spike subunit S1 to recapitulate in vitro studies that Spike enhances the acceleration of amyloid beta aggregation and plaque formation leading to cognitive impairment. This application leverages our ongoing PASC studies in the African green monkey providing all the necessary samples for this investigation. This application also takes advantage of the CoVID-19 NHP Coordinating Center at TNPRC, where three other Centers and we are engaged in Long-CoVID studies and will deposit our data for further analysis. This application represents a novel inquiry into an exciting hypothesis that may provide new insights into novel and effective therapeutic strategies for SARS-CoV-2 infection and PASC.