PROJECT SUMMARY/ABSTRACT Alzheimer’s disease (AD) is the most common neurodegenerative disorder, with low specificity of clinical tests (<70%), due to its pathophysiological process which is largely unknown. Genomic comprehension has been significantly advanced due to the discovery of noncoding RNAs (ncRNAs) as the major product of the transcribed genome. Although recent studies suggest that ncRNAs, especially microRNAs (miRNAs) and long ncRNAs (lncRNAs), are implicated in AD development, only a limited number of miRNAs/lncRNAs- dysregulated pathways were identified, some of which are of dubious relevance to the onset, progression, and pathogenesis of AD. In addition, miRNAs/lncRNAs known to be altered in AD are not always AD-specific, as such changes also occur in other neurodegenerative diseases. Furthermore, the functions of many ncRNAs in AD, especially of emerging ncRNAs, are not known. Our recent experimental data demonstrated that the expression profile of tRNA-derived RNA fragments (tRFs), a recently identified family of ncRNAs, was significantly impacted in AD. Some changes in tRFs were much more significant than changes in miRNAs, and these changes had a pattern of age- and/or stage-dependence in AD patients. Here, we hypothesize that tRFs are key contributors to AD progression and pathogenesis. We will determine tRF signatures associated with AD severity and early-onset AD (Aim 1). We will also identify the targets of aberrant tRFs in AD (Aim 2). Our research experience in the discovery of tRF induction and functions in viral infection and by environmental heavy metal pollutants has provided us with the expertise and tools needed for this project. Our group will also collaborate closely with Dr. Xiang Fang, the Medical Director of the Collaborative AD and Memory Disorders Program at UTMB; and with Dr. Inhan Lee, CEO of miRcore, and an expert in ncRNA bioinformatics; and with a senior biostatistician, Dr. Heidi Spratt, who will oversee statistics analysis and patient sample size determinations. This multidisciplinary research collaboration will help us to achieve our long-term goal of identifying biologically functional molecules that contribute to the onset and progression of AD. We expect this work will also contribute to development of methods for early diagnosis, prevention, monitoring, and potential therapeutic targets for AD.

PROJECT NARRATIVE Non-coding RNAs (ncRNAs, RNAs that cannot be transcribed to proteins) account for about 98% of the transcribed products of human genomes, with biological functions largely unknown. The goal of this project is to determine whether Alzheimer’s Disease (AD)-affected tRFs, a newly discovered family of small ncRNAs (sncRNAs), play a role in the onset and progression of AD.