Assessing the role of lncRNA SLAMR in the pathogenesis of Alzheimers disease - SUMMARY The functions of long-noncoding RNAs (lncRNAs) as crucial regulators of transcription, epigenetic modifications, mRNA stability, localization, and translation indicate their potential involvement in Alzheimer's disease (AD) pathogenesis. Given the impairment of these fundamental cellular processes in AD, lncRNAs emerge as plausible targets. Consistent with this possibility, several studies have demonstrated altered expression of specific lncRNAs in various AD models. However, the precise roles, mechanisms, and cell-specific contributions of these lncRNAs in AD development remain unclear. This exploratory/developmental R21 proposal aims to systematically investigate the regulation of expression and function of lncRNA SLAMR in the pathogenesis of AD. SLAMR lncRNA was discovered from an unbiased screen of learning regulated lncRNAs. We find that SLAMR lncRNA in mouse CA1 is critical for synapse density, morphology, plasticity and memory. Importantly, we find that SLAMR functions as a key modulator of translation and structural plasticity. Gain of function of SLAMR resulted in enhanced translation and functional synapses. Our preliminary data show that SLAMR expression is impaired in APP knock-in (App NL-G-F) mouse model of AD. We will now assess the role of SLAMR mediated translation in App NL-G-F model and Tau model (PS19) of AD. Our systematic functional experiments are anticipated to unveil the role of SLAMR in the progression of AD pathogenesis. Successful completion of this proposal will shed light on the significance of lncRNAs in AD pathogenesis and influence the development of lncRNA-based therapeutics for AD.
