Non-coding RNAs in resilience to Alzheimer’s Disease

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Non-coding RNAs in resilience to Alzheimer’s Disease: PI’s Hide, Kim, Slack Summary (30 lines) This proposal is a response to RFA-AG-23-010 Noncoding RNAs in Alzheimer’s Disease and Related Dementias. The overarching goal of the proposed study is to define and characterize key noncoding RNA (ncRNA) regulators of mechanisms of biological resilience against cognitive loss in Alzheimer’s disease (AD). An individual who is resilient to AD-related neuropathology and does not show cognitive decline despite the presence of AD-related neuropathology will be less likely to develop dementia later in life. A striking natural subpopulation of the elderly remain cognitively intact while controlling or compensating for AD-related pathology. As of yet, drug interventions targeting specific AD-related pathologies, such as β-amyloid, neurofibrillary tangles, or neuroinflammation, have been largely ineffective in controlling AD pathology-related cognitive decline - AD related dementia (AD/ADRD). A compelling alternative is to find ways to enhance resilience against AD/ADRD. During aging, the fidelity of transcriptional regulatory processes declines with associated loss of function and cognitive decline. Proper coding and noncoding gene expression regulation is critical for maintaining homeostasis and preventing disease processes. ncRNAs are increasingly recognized as potent, highly specific regulators of gene expression at all levels. ncRNAs play a critical role in cell stress response. Given the large number of miRNA and lncRNA genes and gene/lncRNA/miRNA interactions and the overarching role of these RNAs in normal processes of the cell, ncRNAs have enormous potential not only as therapeutic targets and biomarkers for the pathologies of aging, but also as key intermediate mechanism markers - helping define mechanisms of disease response that they regulate. We will perform the first study that systematically identifies and characterizes novel ncRNA-regulated resilience mechanisms in AD; derived from human subject data. This project will establish a systematic framework for identification of resilience processes, to explain the roles of ncRNAs in resilience to AD at the cellular and molecular level. Our comprehensive approach will uncover the role of ncRNA factors of resilience to cognitive decline. Using systematic analysis of cognitively resilient populations and powerful tools that identify resilience lncRNAs and miRNAs, we will identify and characterize the interactions, functions and targets of prioritized resilience- associated ncRNAs in our in vitro neuronal/glial cell culture models and advanced three-dimensional (3D) human neural cell culture models of AD. The team brings together broad and deep inter-disciplinary expertise in ncRNA biology, systems biology and Alzheimer’s disease pathology, with a solid basic and translational science background to address understanding of ncRNA in aging (Slack), ncRNA targeting (Vlachos), systems biology of complex disease (Hide) and expertise in 3D AD model systems (Kim) and AD (Tanzi).