HSV‐1 reactivation in AD mouse model reveals longitudinal reduction in synaptic gene expression in the brain

Abstract

AbstractBackgroundMounting evidence supports the contribution of neurotrophic herpesvirus family infections to Alzheimer’s Disease (AD) etiology on the molecular, physiologic, and epidemiologic levels. As chronic viral infections have substantial variability in reactivations, and AD pathology is known to begin over a decade prior to symptoms, understanding the longitudinal impact of herpesviruses on AD pathogenesis is a challenging and complex problem.MethodWe developed a mouse model of herpes‐simplex virus type 1 (HSV‐1) infection in C57B6/J mice containing humanized APP and APOE4. Using 10 mice per group (5 male, 5 female), and after initial infection at 2 months of age via corneal scarification with 106 PFU HSV‐1 strain 17, we reactivated the virus with the bromo‐domain compound JQ1 at 4, 6 and 10 months, with 1x, 3x and 6x reactivations respectively. We included both mock transfected and JQ1‐only treated mice as controls.ResultWe found reactivation by JQ1 resulted in increased HSV‐1 detection by qPCR in a progressive manner, emanating outward from the trigeminal ganglion, towards more distal brain regions. One month post reactivation, we harvested multiple brain regions (brainstem, hippocampus, entorhinal cortex, and dural sinus) for RNAseq expression profiling one month after the last reactivation (i.e. latent HSV‐1 infection) to allow for the immune system to clear the active reactivation and observe long‐term changes in gene expression. We found many synaptic genes down regulated in the entorhinal cortex at 10 months, with 6 reactivations, compared to mock infected. We additionally saw decreases in gene expression in lipid metabolism, myelination, and the endolysosomal pathways. In the brain stem, where HSV‐1 viral levels were found at higher levels, gene expression patterns showed increase immune‐cell related activity.ConclusionOur HSV‐1 reactivation mouse model enables characterization of the impacts of HSV‐1 infections on neuronal gene expression. These changes are consistent with observed changes in gene expression in humans, and help contextualize the putative mechanisms by which HSV‐1 contribute to Alzheimer’s disease etiology.