Project Summary The goal of this project is to better understand the regulation and function of RNA derived from retrotransposable elements (RTEs) in Alzheimer’s disease (AD), with a focus on double-stranded RNAs (dsRNAs). RTEs occupy roughly 40% of the human genome. They constitute a major subgroup of transposons, defined as genomic sequences that mobilize using a ‘copy-and-paste’ mechanism where an RNA intermediate is involved. To date, most RTEs have lost the ability to mobilize to new locations, at least in normal physiological conditions. However, these elements may still retain regulatory activities through expression of RTE-derived RNAs. This functional aspect is particularly relevant in the human brain, where RTE expression is highest compared to other tissues. Given the multi-copy nature of each family of RTEs, their transcripts often form dsRNA structures, resulted from repetitive sequence content, bi-directional transcription or natural sense-antisense transcript pairs. Numerous studies have shown that aberrant expression of cellular dsRNAs is related to the pathogenesis of various human diseases. Recently, increasing evidence supports the existence of enhanced RNA expression from RTEs in neurodegenerative diseases, including AD. This expression leads to accumulation of dsRNAs in neurons, which is correlated with, for example, loss of nuclear TDP-43 or burden of tau tangles. As a result of dsRNA accumulation, type I IFN response may be elicited in neurons, which may contribute to AD pathogenesis. In this project, we aim to determine the identity and origin of AD-relevant dsRNAs derived from RTEs and experimentally validate their functional relevance in neurons. In addition, we will examine the impact of RNA-binding proteins (including ADAR1) on RTE-derived dsRNAs and their functional relevance to AD. This work will allow a previously unattained level of understanding of the regulation and function of RTE-derived dsRNAs in AD and provide new insights to better understand RTE-related disease mechanisms.