Epigenetic gene control in the brain is a fundamental mechanism for orchestrating dynamic gene expression profiles critical for cognitive function. One of the best characterized epigenetic mark crucial for learning and memory is histone acetylation that regulates cognitive gene expression by controlling chromatin packaging in neurons. Appropriate histone acetylation homeostasis is maintained by the antagonistic activity of histone acetyltransferases (HATs) and histone deacetylases (HDACs). Numerous studies, including studies from our lab, have shown that disruption of this finely tuned epigenetic balance in the brain involving reduced histone acetylation levels causes an epigenetic blockade of transcription with concomitant cognitive impairment that is a key step in neurodegenerative disease etiology including Alzheimer's disease (AD). Nevertheless, the specific HATs that generate these neuroepigenetic marks, the gene profiles they regulate, and their mechanisms of action in neural epigenetic gene control in the brain remain largely unknown. Here, we show that disruption of Tip60 HAT/HDAC2 homeostasis occurs early in the brain of an AD associated amyloid precursor protein (APP) Drosophila model and triggers epigenetic repression of neuroplasticity genes well before A[beta] plaques form. Repressed genes display enhanced HDAC2 binding and reduced Tip60 and histone acetylation enrichment. Increasing Tip60 in the AD associated APP brain restores Tip60 HAT/HDAC2 balance by decreasing HDAC2 levels, reverses neuroepigenetic alterations to activate synaptic plasticity genes, and reinstates brain morphology and cognition. Such Drosophila neuroplasticity gene epigenetic signatures are conserved in male and female mouse hippocampus and their expression and Tip60 function is compromised in hippocampus from AD patients. These findings indicate that Tip60 HAT/HDAC2 mediated epigenetic gene disruption is a critical initial step in AD that is reversed by restoring Tip60 in the brain. However, whether such a mechanism is specific to AD or common to other neurodegenerative conditions remains to be identified. Here, we show that disruption of Tip60 HAT/HDAC2 balance is an early event in multiple neurodegenerative Drosophila models including Huntington's Disease (HD), Amyotrophic Lateral Sclerosis (ALS) and Parkinson's Disease (PD) and triggers epigenetic repression of certain subset of synaptic plasticity genes early in the disease. Moreover, larval olfactory associative learning assay displayed significant defects in the learning and memory function, as well as defects in locomotor abilities under neurodegenerative conditions. Importantly, increasing Tip60 HAT activity specifically in the mushroom body of the disease larvae restores defects in complex behaviors including learning and memory and locomotion. Our results support a model by which Tip60 HAT/HDAC2 mediated epigenetic control is critical for normal cognitive function and its disruption is an early event in most neurodegenerative disorders. These studies helped us determine whether Tip60 protects against different neurological impairments via similar modes of action. Our results lay the groundwork for discovering a potentially broad neuroprotective role for Tip60 HAT action in multiple neurological disorders.