The Endogenous Retrovirus (ERV) retroelement family comprises approximately 8% of the human genome. Strong evidence is emerging that abnormal de-repression of normally silenced ERV species, including HUMAN ERV-K (HERV-K), plays a role in age-related neurodegenerative disease, including evidence from both Alzheimer's disease (AD) animal models and post mortem tissue. ERV expression is implicated in a subset of the ?tauopathy? syndromes and those related to TDP-43 proteinopathy, including frontotemporal dementia (FTD). In addition, there is strong evidence that ERVs and LINE-like retrotransposons are increasingly expressed with age in brain and other tissues. The hypothesis that such repetitive, mobile elements contribute to normal aging and to neurodegeneration and AD related dementias is now receiving strong support by a remarkable coalescence of preclinical in vivo work in Drosophila, ex vivo work in mammalian cell culture systems, and postmortem studies in cerebral cortex from human subjects. Unfortunately, to date, there are no mammalian in vivo models to monitor long-term sequels of neuronal ERV expression and replication, including implications for neuronal maintenance and degeneration risk. To provide the field with such type of urgently needed model, we propose a collaborative effort supported by supplemental to a current NIA-sponsored grant (PI Dubnau, RF1AG057338, A systems approach to uncover upstream activators and common downstream pathways of neurodegeneration in a Drosophila model; Project start 09-15-2017, end 06-30-2022) and a current NIMH-sponsored R01 parent grant (PI Akbarian? MH117790-01, Epigenomic Regulation of a Large Neuron-Specific Chromatin Domain, Project start 07-09-2018 , end 05-31-2023). The former is focused on neurodegeneration in a fly ADRD model including impact of retrotransposons and ERVs. The latter on the regulation of the spatially organized neuronal genome in mice with conditional deletion of Kmt1e/Setdb1, a histone methyltransferase for the repressive histone mark, methyl-H3K9.