ABSTRACT Impairment of epigenetic gene control mechanisms in the brain involving reduced histone acetylation levels causes significant cognitive deficits that are a debilitating hallmark of most neurodegenerative disorders, including Alzheimer's disease (AD). Accordingly, of the neural epigenetic modifications identified to date, histone acetylation has been unequivocally linked to facilitating learning and memory by regulating cognition gene expression programs via chromatin packaging control in neurons. Nevertheless, despite the central importance of histone acetylation in higher order brain function, the specific histone acetyltransferases (HATs) that generate these neuroepigenetic marks and their mechanisms of action in neural epigenetic gene control in the brain remain largely unknown. We generated a robust Tip60;APP Drosophila model system that enables us to modulate Tip60 HAT levels in neural circuits of choice under AD associated amyloid precursor protein (APP) neurodegenerative conditions, in vivo. Its use led to our exciting discovery that Tip60 is critical for cognitive processes based on its role in neural epigenetic gene control and remarkably, promotes neuroprotection for multiple cognitive neural circuits impaired in the brain during early AD associated neurodegenerative progression. Further, our new preliminary studies indicate that Tip60 HAT function in cognitive gene control is impaired in the human AD hippocampus. Our findings have laid a solid groundwork for this proposal and our goal for this project is to identify the mechanisms underlying Tip60 HAT action in neuroprotective gene control using fly and mouse AD models, and to determine how these Tip60 epigenetic processes go awry in the brains of human AD patients. We hypothesize that Tip60 promotes neuroprotection during the AD pathological process by epigenetically reprogramming gene sets in the brain that together protect against synaptic impairment and apoptotic cell death, and thus promote cognitive function. Using a combination of molecular, cellular, biochemical and chromatin based techniques, along with behavioral assays, in Aim 1A we will use our Tip60;APP and Tip60;Aβ42 fly models to identify the full array of Tip60 epigenetic reprogrammed genes, and verify their mammalian Tip60 epigenetic conservation in the mouse brain. In Aim 1B we will test whether these Tip60 neuroprotective genes are epigenetically misregulated in the human AD brain, as we predict. In Aim 2A, we will dissect the transcriptional mechanisms for how Tip60 epigenetically reprograms neuroprotective genes using fly and mouse AD models. In Aim 2B we will test whether these same Tip60 transcriptional regulatory complexes are disrupted in the human AD brain, as we predict. Our studies will provide broad insights into novel Tip60 epigenetic mechanisms underlying human neurodegenerative disorders such as Alzheimer's disease, and new understanding into HAT based drug design for early therapeutic interven...