Role of ADAR1 and dsRNA in age-related neuroinflammation and Alzheimers disease

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PROJECT SUMMARY The purpose of this F31 proposal is to provide support for Cali McEntee, a doctoral student at Colorado State University (CSU), while she trains to become an independent scientist conducting research on age-related neurodegeneration. With support from this award, Ms. McEntee will determine if reductions in adenosine deaminase acting on RNA 1 (ADAR1) lead to the accumulation of double-stranded RNA (dsRNA), a pathogen-associated molecular pattern that causes innate immune/inflammatory signaling, in the context of brain aging and Alzheimer’s disease (AD). Numerous reports show that ADAR1 suppresses dsRNA-related inflammation and may modulate lifespan, and that innate immune activation/neuroinflammation driven by glial cells, like astrocytes, is a central mechanism of brain aging/AD. The applicant’s preliminary data show that brain aging/AD are associated with reductions in ADAR1 levels, and that reducing ADAR1 expression in astrocytes leads to an increase in transcripts from genomic repetitive elements (RE), which are increasingly implicated in aging and neurodegeneration and predisposed to form dsRNA. As such, ADAR1 may be an important regulator of neuroinflammation with brain aging and/or AD, perhaps by reducing RE-associated dsRNA accumulation. However, this idea has not been investigated. In this project, Ms. McEntee proposes to gain valuable translational research training by using multiple models to test the hypothesis that ADAR1 reduces the deleterious effects of RE-derived dsRNA and thereby protects against age/AD-related neuroinflammation by: Aim 1) using directly reprogramed human astrocytes from healthy young/older adults and AD patients to determine if ADAR1 and dsRNA levels are related to neuroinflammation, performing total RNA-seq and RNA immunoprecipitation sequencing (RIP-seq) to identify RE-derived dsRNAs involved in neuroinflammation, and intersecting her findings with existing clinical datasets; and Aim 2) increasing expression of ADAR1 in reprogrammed human astrocytes and a pre-clinical mouse model of aging to determine if ADAR1 protects against age/AD-related neuroinflammation and cognitive dysfunction. Ms. McEntee’s immediate goal is to gain the fundamental experience and professional skills necessary to perform independent research in the field of age-related neurodegenerative diseases. Her long-term goal is to become an academic, translational researcher investigating mechanisms of aging that contribute to neurodegenerative disease. Ms. McEntee will train in a state-of-the-art environment with an exceptional mentoring team at CSU. The sponsor, Dr. LaRocca, has an extensive background studying aging and neurodegenerative diseases and directs the NIH-funded Healthspan Biology Laboratory at CSU. Under the guidance of Dr. LaRocca and consulting mentors Drs. Chris Link, Ron Tjalkens, Julie Moreno, and Dan Lark, Ms. McEntee will be able to successfully complete the training plan, supporting her development into an independent scientist.