Analysis of human endogenous retrovirus in Alzheimer’s disease and Frontotemporal dementia affected tissues

Abstract

AbstractBackgroundHuman Endogenous Retroviruses (HERVs), normally dormant within the eukaryotic genome, can be awaken by environmental factors that may induce neurodegeneration via brain inflammation and epigenetic dysregulation. We investigated different HERVs transcripts using blood and post‐mortem brain samples from genetic and sporadic Alzheimer’s disease (gAD and sAD) and Frontotemporal Dementia (sFTD and gFTD) patients, using quantitative PCR (RT‐qPCR) and microarray techniques. Only HERV‐K env transcript was upregulated in sporadic AD in blood. Genome‐wide DNA methylation data analysis revealed hypermethylation in several genes involved in HERVs machinery, including APOBEC3, CDK6, E2F5, PRODH and SLC4A8 in AD and FTD when compared to healthy controls in post‐mortem brain tissue. In summary, our preliminary findings suggest that HERVs may be implicated in AD and FTD neuropathogenesis.MethodRNA samples were obtained from sAD (n = 63), gAD (n = 10), sFTD (n = 46), gFTD (n = 15) and healthy controls (n = 39). Post‐mortem tissue (prefrontal cortex) from sAD (n = 10), gAD (n = 10), sFTD (n = 10), gFTD (n = 15) and healthy controls (n = 17). Quantification of different HERVs were measured by qRT‐PCR. Transcript levels within each of the samples were quantitated and normalized using the reference genes actin and GAPDH. 64 subjects were studied with Infinium MethylationEPIC array. Samples comprised healthy controls (n = 5), sAD (n = 5), gAD (n = 5), gFTD (n = 15) and sFTD (n = 10).ResultHERV‐K env transcript was increased in blood from sAD compared to healthy controls (p = 0.0044). No other HERV transcript was found to be significantly upregulated in sporadic and genetic AD and FTD. Microarray analysis from AD and FTD patients revealed hypermethylation in APOBEC3, E2F5, in all groups and CDK6, PRODH and SLC4A8 in FTD when compared to healthy controls in post‐mortem brain tissue.ConclusionIn this study we found that HERV‐K env transcript was upregulated in sAD from blood, which could be useful as a potential clinical biomarker. Future studies targeting the env protein should be performed to confirm the results found in this preliminary study. Hypermethylation of different genes involved in HERVs machinery suggest a different pathomechanism between AD and FTD that might help to differentiate them. Future functional studies for APOBEC3, CDK6, E2F5, PRODH and SLC4A8 could reveal the underlying biological mechanism leading to HERV activation.