Project Summary We propose experiments to rigorously investigate whether lncRNAs influence gene transcription programs in the hippocampus in response to Alzheimer’s disease (AD) pathology, and the potential of lncRNAs to be therapeutically leveraged to promote memory resiliency in AD. AD progression involves profound disruptions in gene transcriptional programs in the hippocampus, the brain region necessary for learning and memory. Epigenetic interventions to enhance memory resilience in AD are possible. However, it is not well-understood how abnormal epigenetic control of gene transcription contributes to AD-related memory deficits. We and others have demonstrated that epigenetic chromatin remodeling mechanisms, like posttranslational modifications of histones, DNA methylation, and non-coding RNAs are crucial for the regulation of memory-permissive genes in the hippocampus during memory formation. Currently, a significant gap in knowledge exists regarding the role of long non-coding RNAs (lncRNAs) in memory formation in the healthy brain and how it is altered in AD-related memory dysfunction. Our long-term goal is to study the role of lncRNAs in a cell-type specific manner and to identify how these powerful epigenetic regulators impact memory formation in AD. Our pilot data demonstrate that Neat1 is overexpressed in area CA1 of the hippocampus from the hAPP-J20 AD model. Furthermore, we demonstrate that inhibiting Neat1 expression in area CA1 of the hippocampus of the hAPP-J20 AD model reverses memory impairments. Pilot studies also suggest a strong relationship between histone methylation mechanisms with Neat1 overexpression in the hAPP- J20 AD model. Based on these preliminary results, we plan to examine the effects of manipulating Neat1 in the hippocampus and determine effects on AD-related memory decline. To gain further mechanistic insight into Neat1 mediated gene transcription in the hippocampus of AD mouse models, we will use state-of-the-art approaches such as single nuclei RNA isolation followed by sequencing and Chromatin Isolation by RNA Purification to elucidate the cell-type specific epigenetic mechanisms coupled to lncRNAs in our AD animal models. Our overarching hypothesis is that Neat1 contributes to AD-associated transcriptional changes in hippocampal cells, hippocampal function, and vulnerability to memory dysfunction. Our Specific Aims are as follows: Specific Aim 1: Test the hypothesis that Neat1 impacts AD pathology in the hippocampus; Specific Aim 2: To determine the necessity of Neat1 on AD responsive gene transcription programs in the hippocampus; Specific Aim 3: To identify the mechanisms by which Neat1 contributes to chromatin restructuring in AD; and Specific Aim 4: To test whether hippocampal Neat1 dysregulation contributes to AD-related memory dysfunction. Collectively, these studies will have broad implications for treatment options for AD associated cognitive decline.