Role of age-associated epigenetic repetitive element derepression in Alzheimer's Disease

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PROJECT SUMMARY Age is the primary risk factor for sporadic (i.e., age-related, not genetic/familial) Alzheimer’s disease (AD), and neuroinflammation is a key driver of brain aging and AD. Recent advances in next-generation sequencing (e.g., RNA-seq/transcriptomics) may help to identify causes of age/AD-related neuroinflammation; however, most transcriptome studies of aging have largely focused on coding genes, while non-coding repetitive sequences (which represent >50% of the human genome) have been largely ignored. Growing evidence from our lab and others shows that expression of repetitive element (RE) transcripts increases with age and may contribute to aging/AD, but the exact mechanisms by which RE dysregulation occurs are incompletely understood. One possibility is that epigenetic changes (which are an established feature of aging/AD) may be involved. How these epigenetic changes contribute to RE transcript accumulation is unclear, but there are two possibilities: 1) age-associated changes in chromatin structure and loss of heterochromatin (highly compact and inaccessible); or 2) reduced DNA methylation of REs. Both of these epigenetic changes could increase activation/expression of REs that are normally suppressed, and both could represent novel therapeutic targets. In this F31 application, the candidate, Alyssa Cavalier, proposes to gain valuable translational research training by using a “multi-omics approach” to study epigenetic dysregulation of RE transcripts and their role in aging, neuroinflammation and AD. She will take advantage of existing samples to generate chromatin accessibility and whole genome methylation sequencing data, and use bioinformatics analyses to determine if REs increased with aging/AD originate from genomic regions that show epigenetic dysregulation. Her immediate goal is to gain the fundamental experience and professional skills necessary to perform independent research. Her long-term goal is to become an academic, translational scientist investigating the biological mechanisms of brain aging and neurodegeneration. Ms. Cavalier will train in a state-of-the-art environment with an exceptional mentoring team at Colorado State University (CSU). The sponsor, Dr. Tom LaRocca, has an extensive background studying aging and RE, and directs the NIH-funded Healthspan Biology Laboratory at CSU. Consulting mentors Drs. Chris Link, Karyn Hamilton, and Brianne Bettcher will provide expertise on topics ranging from molecular to clinical research to prepare Ms. Cavalier for a career as a translational scientist. Ms. Cavalier’s career development plan consists of: 1) training in bioinformatics, biostatistics and interpretation/analyses of clinical data; 2) learning state-of-the-art wet-lab techniques to develop her translational research skills; 3) strengthening and broadening her molecular biology skillset; and 4) further developing her professional skills through interaction with her mentoring team, coursework, weekly lab meetings, and scientific conferences.