Human herpesvirus‐associated transposable element activation in human aging brains with Alzheimer's disease

Abstract INTRODUCTION Human herpesvirus (HHV) has been linked to Alzheimer's disease (AD), but the underlying mechanisms remain unknown. METHODS We leveraged functional genomics data from Religious Orders Study or the Rush Memory and Aging Project (ROS/MAP) and Mount Sinai Brain Bank (MSBB) brain biobanks and single‐cell RNA‐sequencing data from HHV‐infected forebrain organoids to investigate HHV‐infection‐associated transposable element (TE) dysregulation underlying AD etiologies. RESULTS We identified widespread TE dysregulation in HHV‐positive human AD brains, including an astrocyte‐specific upregulation of LINE1 subfamily TEs in HHV‐positive human AD brains. We further pinpointed astrocyte‐specific LINE1 upregulation that could potentially regulate target gene NEAT1 expression via long‐range enhancer‐promoter chromatin interactions. This LINE1 dysregulation can be partially reversed by the usage of anti‐HHV drugs (valacyclovir and acyclovir) in a virus‐infected human brain organoid model. Finally, we demonstrated that valacyclovir rescued tau‐associated neuropathology and alleviated LINE1 activation in an experimental tau aggregation model. DISCUSSION Our analysis provides associations linking molecular, clinical, and neuropathological AD features with HHV infection, which warrants future clinical validation. Highlights Via analysis of bulk RNA‐seq data in two large‐scale human brain biobanks, ROS/MAP ( n = 109 pathologically confirmed AD and n = 44 cognitively healthy controls) and MSBB ( n = 284 AD and n = 150 cognitively healthy controls), we identified widespread TE activation in HHV‐positive human AD brains and significantly positive associations of HHV RNA abundance with APOE4 genotype, Braak staging score, and CERAD score. We identified cell type‐specific LINE1 upregulation in both microglia and astrocytes of human AD brains via long‐range enhancer–promoter chromatin interactions on lncRNA nuclear enriched abundant transcript 1 ( NEAT1 ). We determined that usage of valacyclovir and acyclovir was significantly associated with reduced incidence of AD in a large real‐world patient database. Using the HEK293 tau P301S model and U2OS mt‐Keima cell model, we determined that valacyclovir treatment rescued tau‐associated neuropathology and alleviated activation of LINE1 with increased cellular autophagy‐level mechanistically supported clinical benefits of valacyclovir in real‐world patient data.