Restoring Tip60 HAT/HDAC2 Balance in the Neurodegenerative Brain Relieves Epigenetic Transcriptional Repression and Reinstates Cognition

Abstract

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) model 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. Such 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. 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. Mild 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 AD brain 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.

Disruption of Tip60 HAT mediated neural histone acetylation homeostasis is an early common event in neurodegenerative diseases

“…In line with these studies, we previously reported decreased levels of the HAT, Tat interactive protein 60 kDa (Tip60), and concomitant loss of Tip60 associated specific histone acetylation marks in an AD Drosophila model and in human postmortem AD brain. We further demonstrated that increasing Tip60 levels in the AD Drosophila brain protects against alteration of Tip60 HAT/HDAC2 balance, epigenetic-mediated neuroplasticity gene repression and functional cognitive deficits that occur during early stages of neurodegenerative progression 17 . These findings raise the possibility that Tip60 HAT/HDAC2 imbalance may be an early common event that contributes to epigenetic mediated gene misregulation and cognition deficits in other NDs as well.…”

“…Tip60 HAT action improves short-term memory deficits in PD larvae. Our previous findings demonstrated that increasing Tip60 HAT activity partially suppresses learning and memory associated defects in www.nature.com/scientificreports/ the AD Drosophila larval and adult brain 17,45 . However, whether such cognitive deficits also occur early in other neurodegenerative disorders and can be prevented by increasing Tip60 HAT levels in the brain remain to be elucidated.…”

Blocking H2A.Z Incorporation via Tip60 Inhibition Promotes Systems Consolidation of Fear Memory in Mice

“…The effects of Tip60 on H2A.Z binding in the brain has implications for recent studies showing that Tip60 regulates neural plasticity, presumably through its role as a HAT ( Xu et al, 2016 ; Uchida et al, 2017 ; Panikker et al, 2018 ). Our data implicate H2A.Z deposition as another downstream target of Tip60 that may mediate some of its previously reported effects in the brain.…”

Lysophospholipids and Their G-Coupled Protein Signaling in Alzheimer’s Disease: From Physiological Performance to Pathological Impairment

“…Since SphK2 and S1P have been indicated to regulate the expression of HDAC1/2, there is also evidence suggesting that S1P acts as an underlying epigenetic regulator in AD-related cognitive dysfunction. Graff et al (2012) have demonstrated in their study that elevated levels of HDAC2 could epigenetically repress the synaptic genes that related to cognitive deficits, while Panikker et al (2018) suggested that decreasing HDAC2 levels in AD-related APP brain could reverse the neuroepigenetic changes in activating synaptic plasticity genes, as well as restoring brain morphology and cognition (Graff et al, 2012;Panikker et al, 2018).…”