Identification and Characterization of Cell-Specific Transposable Elements Implicated on Alzheimer Disease and Healthy Aging

Abstract Alzheimer disease (AD) is the most common form of dementia and neurodegeneration affecting more than 5 million Americans with no current effective treatment. Several Mendelian mutations and risk variants have been identified. We and others have shown that AD is associated with changes in brain cell proportion and transcriptomic changes, some of them are also cell specific. Additionally, the latest genetic studies implicate cell-specific pathogenic events that lead to disease. Pathogenic variants in APP, PSEN1 and PSEN2 affects APP processing leading to Aβ aggregates and neuronal death. Genetic variants in TREM2 and MS4A modify AD risk by affecting microglia activity. To fully understand and characterize the role of transposable elements (TE) in AD pathogenesis there is a need to novel and multidisciplinary approaches. Here we will combine novel genomic approaches in human brain tissues, direct converted neurons and iPSC-derived microglia (iMGL) to identify cell-specific TE and downstream (chromatin accessibility, transcription) changes implicated in AD. We will leverage a large and unique resources of human brain samples and fibroblast from individuals with mutations in APP, PSEN1, PSEN2, as well as risk variants in TREM2, MS4A or APOE. We will also use the direct converted neurons and iMGL, together with new genomic editing approaches to target and characterize the mechanism by which TE contribute to disease.