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Cognitive impairment is a debilitating hallmark during pre-clin- ical stages of Alzheimer’s disease (AD) yet causes remain un- clear. As histone acetylation homeostasis is critical for early developmental epigenetic gene control, we postulated that its misregulation contributes to cognitive deficits preceding AD pathology. Here, we show that disruption of Tip60 HAT/ HDAC2 homeostasis occurs early in the AD Drosophila brain and trig- gers epigenetic repression of a group of synaptic genes well before Aβ plaques form. Repressed genes display enhanced HDAC2 binding and reduced Tip60 and histone acetylation enrichment. Increasing Tip60 in the AD brain restores Tip60 HAT/HDAC2 balance, reverses neuroepigenetic alterations to activate synaptic genes, and reinstates brain morphology and cognition. Importantly, levels of Tip60, neuroepigenetic acetyl- ation marks and activation of these same synaptic genes are significantly reduced in hippocampus from AD patients. Ge- nomic reorganization of transcription factories (TFs), charac- terized as specialized nuclear subcompartments enriched in hyperphosphorylated RNAPII and transcriptional regulatory proteins, act as an additional layer of control in coordinating ef- ficient co-regulated gene transcription. Thus, we asked wheth- er Tip60 utilized this mechanism in its epigenetic control of ac- tivity-dependent co-regulated synaptic genes in the brain. Our findings reveal that Tip60 shuttles into the nucleus following extracellular stimulation of rat hippocampal neurons with con-comitant enhancement of Tip60 binding and activation of the same synaptic genes we identified as repressed in the Drosoph- ila and human AD brain.
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