Alzheimer's Disease and Related Dementia-like Sequelae of SARS-CoV-2 Infection: Virus-Host Interactome, Neuropathobiology, and Drug Repurposing

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PROJECT SUMMARY Abundant cross-interdisciplinary evidence indicates that there are multiple pathophysiological processes driving development and progression of Alzheimer’s disease (AD) and AD-related dementias (ADRD), including neuroinflammation and microvascular injury to pathogens, especially viruses. We are examining these aspects of AD/ADRD with respect to human coronavirus disease 2019 (COVID-19), which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with over 87 million cases in the United States alone. Notably, substantial evidence indicates neurocognitive sequelae of COVID-19, which are poised to ultimately lead to a surge in cases of AD/ADRD, and other forms of neurocognitive impairment. Preliminary evidence from our team identified that SARS-CoV-2 infection caused neuroinflammation and brain microvascular injury, two major risk factors for AD/ADRD. We have also demonstrated that systematic characterization of human- and virus- human protein interactome maps can identify novel pathophysiological pathways and drug targets to protect the SARS-CoV-2-infected brains. We therefore posit that multimodal analyses of SARS-CoV-2-human interactome maps in patient induced pluripotent stem cell (iPSC)-derived brain microvascular endothelial cells (BMECs) and brain single-nucleus genomic/epigenomic data from de novo AD/ADRD-like neurocognitive impairment in COVID-19 patients (Neurocogn-COVID), will provide valuable unbiased insights into the complex etiology of neurocognitive sequelae of SARS-CoV-2 at molecular, cellular and network levels. This project will elucidate critical understanding of both brain cell type-specific virus-human protein interactome-inhibitory targets and neuro-immune gene networks and brain microvascular injury that may lead to AD/ADRD after viral infection. Our immediate goal is to build a comprehensive, brain cell type-specific virus-human protein interactome map for identifying molecular drivers for neurocognitive sequelae of SARS-CoV-2 infection using our high-throughput protein interactomics platform. Aim 1 will interrogate the SARS-CoV-2 virus-human interactome to identify and validate molecular drivers of ADRD-like viral microvascular injury in iPSC-derived BMECs (age-, sex-, APOE- matched iPSC lines). Aim 2 will interrogate cell type-specific neuroimmune and brain endothelial transcriptional networks to identify pathophysiology related to virus-induced neuro-inflammation and brain microvascular injury. We will leverage single-nucleus genomic/epigenomic data generated from brain tissues of donors who suffered from neurocogn-COVID, AD, mild cognitive impairment (MCI), and age-, sex-, APOE-matched healthy controls from the Cleveland Alzheimer's Disease Research Center (ADRC) and Northwestern ADRC. Aim 3 will test the hypothesis that potential new opportunities for drug repurposing in neurocognitive sequelae can be identified through a combination of longitudinal population-based validation and functional testing in mouse models. Successful completion of this project will elucidate mechanistic biomarker for neurocognitive sequelae of SARS- CoV-2 and identify new drug targets and treatments to be directly tested in clinical trials. 1