Investigation of herpesviruses in dementia patients and associated inflammatory gene modulation

Abstract

AbstractBackgroundAlzheimer’s disease (AD) and vascular contributions to cognitive impairment and dementia (VCID) are the leading causes of dementia worldwide, with the two frequently found co‐morbid in dementia patients at autopsy. Studies have connected multiple herpesviruses to the development and pathogenesis of AD. The goal of this study was to determine the prevalence of four common herpesviruses in a cohort of AD and VCID patients, and to identify differential gene expression as a function of viral presence. We hypothesize AD and VCID cases will possess more latent virus than control cases, and cases with latent virus present will show a down‐regulation of innate immune related genes, and an upregulation of cell survival genes and transcriptional suppressors.MethodUsing droplet‐based PCR, we quantified the prevalence of four herpesviruses (herpes simplex virus 1, herpes simplex virus 2, cytomegalovirus, and human herpes virus 6) in a subset of brain autopsy tissue obtained from the Sanders‐Brown Center on Aging Alzheimer’s Disease Center (UK‐ADC). RNA and genomic DNA was extracted from the superior medial temporal gyrus and cerebellum of 49 cases (n=18 control, n=10 vascular pathology, n=20 AD, n=1 mixed AD+VCI). Genomic DNA was used to determine the presence of latent virus and cDNA to determine actively replicating virus. The RNA from these regions was run on the NanoString neuroinflammatory panel which quantifies a number of genes, ranging from neuroinflammatory markers to cell specific functional genes.ResultWe identified an increased amount of latent viral populations in the AD patients relative to control patients. NanoString analysis supported our initial hypothesis regarding gene regulation relating to innate immunity and cell survival, but we also observed downregulation of insulin‐like growth factor, synapse‐associated protein 97, and cell death‐inducing DFFA‐like effector b in the presence of certain latent viral populations.ConclusionOur results demonstrate the prevalence of herpesviruses within an AD cohort, supporting research suggesting a link between the two. Further, it shows alterations in the expression of neuroinflammatory genes as a function of latent virus presence.