Human endogenous retroviruses are upregulated in Frontotemporal Dementia-MAPT mutation carriers

Abstract

Abstract Previous studies have identified an upregulation of human endogenous retroviruses (HERVs) in several disorders, but little is known about their role in neurodegenerative dementias. In this study, we investigate a possible role of HERVs in the pathogenesis of sporadic and genetic frontotemporal dementia (FTD) and Alzheimer’s disease (AD). We measured HERVs transcripts using quantitative reverse transcription PCR (qRT-PCR) in post-mortem prefrontal cortex tissue samples from individuals with sporadic FTD (sFTD), genetic FTD (gFTD), sporadic AD (sAD), genetic AD (gAD) and healthy controls and then analysed RNA from whole blood from individuals with gFTD and controls. We also evaluated HERVK-env protein levels by an enzyme-linked immunosorbent assay (ELISA) in post-mortem brain FTD-MAPT mutation carriers and controls. We further analysed DNA methylation microarrays data from sFTD and gFTD patients looking for alterations in HERV-interacting genes. We show that in FTD-MAPT post-mortem brain tissue, HERVK (pol, gag, env and env3), HERVR-env and HERVW-env transcripts were upregulated with a fold-change (FC) > 2. In the other groups, HERVK-pol and HERVR-env transcripts were significantly upregulated in sFTD with tau deposits, sAD, and gAD patients, compared to controls, but the fold-change (FC) was lower than 2. HERVK-env protein was significantly elevated in FTD-MAPT brain compared to controls. We found several differentially methylated CpGs in interacting-HERVs genes (NUPR1, PGBD5, CBX1, CBX3, and ARC) in FTD-MAPT carriers compared to healthy subjects. In contrast, RNA from whole blood displayed decreased expression of HERVK-pol, HERVK-gag, HERVK-env3 and HERVW-env in FTD-MAPT compared to controls. These results strongly suggest that brain HERVs upregulation is associated with FTD-MAPT pathology. We hypothesize that HERV activity could serve as a potential target for antiviral drug administration in human FTD-MAPT carriers.