ABSTRACT Alzheimer’s disease (AD) is a debilitating progressive neurodegenerative disorder (ND) hallmarked by initial mild cognitive impairment (MCI) followed by dementia. The severity of AD progression is dependent upon the complex interplay between genetics, age, and environmental factors orchestrated in large part, by epigenetic histone acetylation (HA) mediated gene regulatory mechanisms. HA homoeostasis in the brain is maintained by antagonizing histone acetyltransferase (HAT) and histone deacetyltransferase (HDAC) enzymes that generate and erase cognition-linked histone acetylation marks, respectively. Reduced HA levels in the brain cause chromatin packaging alterations in neurons, with concomitant transcriptional dysregulation that is a key initial step in AD etiology. Nevertheless, the specific HATs that generate these distinct neuroepigenomic acetylation signatures in the brain, and thus serve as causative agents underlying memory impairing HA alterations in AD, remain largely unknown. Our laboratory has a long-standing interest in the HAT Tip60 as an epigenetic mediator of neural transcriptional regulatory responses in cognition and AD. We generated a robust APP;Tip60 Drosophila model system that enables us to modulate Tip60 HAT levels in neural circuits of choice under AD amyloid precursor protein (APP) neurodegenerative conditions, in vivo. Its use led to a compendium of published studies that establish a central role for Tip60 HAT mediated chromatin dynamics in cognitive function and neuroprotection in AD. During this funding period, we also made several separate and striking discoveries regarding alternative novel cellular mechanisms for Tip60 in mediating neuronal gene control that are disrupted in AD. These include: (1) experience-dependent (ED) Tip60 nucleocytoplasmic transport (NCT) and (2) a novel RNA-binding function for Tip60. The overarching goal of this proposal is to elucidate these new Tip60 functions, as well as generate novel Tip60 specific therapeutic compounds, to deepen our understanding of Tip60’s unique roles in nervous system biology and AD neuroprotection. To achieve this research goal, our team combines expertise in the unique but complementing areas of Tip60 function in cognition and AD (Elefant, PI), neuroepigenetics in RNA splicing (Heller, CoI) and novel drug discovery (Kortegare, CoI) to propose the following specific aims: In Aim 1 we functionally assess Tip60 nucleocytoplasmic transport (NCT) in neuronal experience- dependent gene control. In Aim 2 we dissect a novel bi-level neuronal function for Tip60 at the chromatin and RNA splicing level in †he brain. In Aim 3 we will generate novel Tip60 based therapeutic compounds to identify cognitive benefits of pharmacologically enhancing human Tip60’s HAT activity. Successful completion of this project will uncover novel molecular pathways, targets and early biomarkers to treat AD and generate a specific Tip60 HAT activator compound with AD neuroprotection cap...