Research Project
10302457
Aging increases the risk for Alzheimer?s disease (AD), but the underlying mechanisms are poorly understood. Next-generation sequencing studies (e.g., transcriptomics, RNA-seq) hold promise for identifying novel mediators of brain aging/AD, but many have focused on coding genes only. Therefore, in response to PAS-19-392, which emphasizes the ?elucidation of genetic and epigenetic factors, genome stability, damage, and DNA repair? in AD, in this R03 project we will explore an emerging topic in genome biology that may provide insight into novel mechanisms of brain aging/AD. Specifically, we will determine if an age-related accumulation of non-coding repetitive element (RE) transcripts is an important link between brain aging and AD, and we will test related therapeutic strategies. Our rationale is that RE transcripts are predisposed to form double-stranded RNA (dsRNA) that may stimulate neuroinflammation (a major and potentially targetable mechanism of AD). RE transcripts are derived from non-coding repetitive sequences that make up >60% of the human genome. They are often ignored in transcriptome studies as ?inactive?. However, growing evidence demonstrates that dysregulation/activation of RE contributes directly to aging, and that certain pharmacological interventions may prevent their effects. Some evidence also indicates that select RE transcripts are increased in AD, but our preliminary data show that: a) global RE transcript levels (i.e., not just select RE) increase progressively with age in human peripheral tissues, brains and neurons, and are associated with greater dsRNA; b) similar RE transcripts and dsRNA are increased in AD patient brains and neurons; and c) RE transcript suppression may inhibit neuro-inflammatory signaling. These observations suggest that an age-related, global dysregulation of RE transcripts could play a central role in brain aging and age-related AD, perhaps by causing dsRNA-driven neuroinflammation. We will investigate this possibility by: 1) conducting a large-scale bioinformatics analysis of multiple RNA-seq datasets to identify key RE transcripts and RE-derived dsRNAs associated with brain aging/AD and neuroinflammation; and 2) using neurons derived from human donors to test the efficacy of clinically translatable, phytochemical compounds that reduce RE/dsRNA accumulation for inhibiting age/AD- related neuroinflammation, and to identify the RE-derived dsRNAs that may cause neuroinflammation and AD by stimulating the cellular dsRNA sensor protein kinase R (PKR, which has been linked with AD pathology). These studies will provide a framework for a future R01 investigating the specific mechanisms by which age- related RE transcript increases contribute to brain aging/AD and the potential for RE-targeting therapies to treat or prevent brain aging/AD in vivo.
