Alzheimer's Disease associated pathology induced by neurotropic viral infection

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SUMMARY Genetic risk factors for Alzheimer's Disease can predict the increased likelihood of acquiring the disease yet it is becoming more evident that external factors are involved in the neurodegenerative disease progression. Recently two herpesviruses have been implicated in this disorder as they have been found in diseased tissues of Alzheimer's patients. Human herpes simplex virus 1 (HSV-1) and Human Herpesvirus 6a (HHV6a) are neurotropic herpesviruses that establish both lytic and lifelong latent infections of the nervous system. How these viral pathogens alter the outcome of neurodegenerative disease remains uncharacterized. Alzheimer's Disease is marked by distinct alterations of host proteins including the misfolding of Tau. Using a novel human iPSC-derived 3D cortical model system, we observed altered splicing of the mRNA that encodes Tau. Additionally, we observe a viral infection dependent increase in the accumulation of phospho-Tau, a post translational modification indicating the misfolding of Tau. These preliminary findings support the hypothesis that viral infections directly impact the host cell microenvironment resulting in changes in Alzheimer's Disease markers. The overarching goal of these studies is to identify infectious etiological agents that impact either the severity or frequency of Alzheimer's Disease progression. The objective of this proposal is to define the biological impact of neurotropic herpesvirus infections on accumulation of known drivers of Alzheimer's disease within a physiologically relevant model system. Our first aim will identify and define viral dependent changes within multiple host proteins involved in neurodegeneration. This will for the first time, a direct link between neurotropic virus infections and pathogenic neurodegenerations in cells of clinical relevance. The second aim will use novel RNA labeling protocols to profile the transcriptome from only infected cells within the 3D organoids and will utilize single cell sequencing to characterize the tropism of these neurotropic viruses. The third aim will utilize 3D organoids that harbor known genetic risk factor mutations found in the onset of Alzheimer's Disease and will determine if herpesviruses amplify the onset of neurodegenerative progression. Successful completion will clearly define the viral factors that influence Alzheimer's disease and will provide insight in pathogenic mechanisms that extend beyond Alzheimer's Disease.