Restoring Tip60 HAT/HDAC2 Balance in the Neurodegenerative Brain Relieves Epigenetic Transcriptional Repression and Reinstates Cognition
| Autor: | Mariah Beaver, Jessica Sarthi, Song-Jun Xu, Sunya Akhter, Priyalakshmi Panikker, Haolin Zhang, Avni Sheth, Felice Elefant |
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| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine Histone Deacetylase 2 Plaque Amyloid Epigenetic Repression Lysine Acetyltransferase 5 Mice 03 medical and health sciences Neuroplasticity Amyloid precursor protein Animals Homeostasis Humans Learning Epigenetics Cognitive decline Research Articles Aged 80 and over Neuronal Plasticity biology Histone deacetylase 2 General Neuroscience Neurodegenerative Diseases Mice Inbred C57BL Smell Drosophila melanogaster 030104 developmental biology Histone Synaptic plasticity biology.protein Female Cognition Disorders Neuroscience |
| Zdroj: | The Journal of Neuroscience. 38:4569-4583 |
| ISSN: | 1529-2401 0270-6474 |
| DOI: | 10.1523/jneurosci.2840-17.2018 |
| Popis: | Cognitive decline is a debilitating hallmark during preclinical stages of Alzheimer's disease (AD), yet the causes remain unclear. Because histone acetylation homeostasis is critical for mediating epigenetic gene control throughout neuronal development, we postulated that its misregulation contributes to cognitive impairment preceding AD pathology. Here, we show that disruption of Tip60 histone acetlytransferase (HAT)/histone deacetylase 2 (HDAC2) homeostasis occurs early in the brain of an AD-associated amyloid precursor protein (APP)Drosophilamodel and triggers epigenetic repression of neuroplasticity genes well before Aβ plaques form in male and female larvae. 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. SuchDrosophilaneuroplasticity gene epigenetic signatures are conserved in male and female mouse hippocampus and their expression and Tip60 function is compromised in hippocampus from AD patients. We suggest that Tip60 HAT/HDAC2-mediated epigenetic gene disruption is a critical initial step in AD that is reversed by restoring Tip60 in the brain.SIGNIFICANCE STATEMENTMild cognitive impairment is a debilitating hallmark during preclinical stages of Alzheimer's disease (AD), yet its causes remain unclear. Although recent findings support elevated histone deacetylase 2 (HDAC2) as a cause for epigenetic repression of synaptic genes that contribute to cognitive deficits, whether alterations in histone acetlytransferase (HAT) levels that counterbalance HDAC2 repressor action occur and the identity of these HATs remain unknown. We demonstrate that disruption of Tip60 HAT/HDAC2 homeostasis occurs early in the ADDrosophilabrain and triggers epigenetic repression of neuroplasticity genes before Aβ plaques form. Increasing Tip60 in the AD brain restores Tip60 HAT/HDAC2 balance, reverses neuroepigenetic alterations to activate synaptic genes, and reinstates brain morphology and cognition. Our data suggest that disruption of the Tip60 HAT/HDAC2 balance is a critical initial step in AD. |
| Databáze: | OpenAIRE |
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