Tip60 HAT Action Mediates Environmental Enrichment Induced Cognitive Restoration

Abstract

Environmental enrichment (EE) conditions have beneficial effects for reinstating cognitive ability in neuropathological disorders like Alzheimer’s disease (AD). While EE benefits involve epigenetic gene control mechanisms that comprise histone acetylation, the histone acetyltransferases (HATs) involved remain largely unknown. Here, we examine a role for Tip60 HAT action in mediating activity- dependent beneficial neuroadaptations to EE using the Drosophila CNS mushroom body (MB) as a well-characterized cognition model. We show that flies raised under EE conditions display enhanced MB axonal outgrowth, synaptic marker protein production, histone acetylation induction and transcriptional activation of cognition linked genes when compared to their genotypically identical siblings raised under isolated conditions. Further, these beneficial changes are impaired in both Tip60 HAT mutant flies and APP neurodegenerative flies. While EE conditions provide some beneficial neuroadaptive changes in the APP neurodegenerative fly MB, such positive changes are significantly enhanced by increasing MB Tip60 HAT levels. Our results implicate Tip60 as a critical mediator of EE-induced benefits, and provide broad insights into synergistic behavioral and epigenetic based therapeutic approaches for treatment of cognitive disorder.

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.…”

The Therapeutic Potential of Epigenetic Modifications in Alzheimer’s Disease

“…Another mechanism for enhancing acetylation is the use of drugs that enhance HATs. The increased expression of an enzyme of this type, Tip60, in drosophila overexpressing human APP was able to restore the benefits of environmental enrichment (61).…”

Roles of the MYST Family in the Pathogenesis of Alzheimer’s Disease via Histone or Non-histone Acetylation

“…To determine the molecular mechanisms underlying the neuroprotective function of Tip60, ChIP-seq analysis has identified a variety of cognitive genes that are dysregulated in Tip60-mutant flies [ 28 ]. Additionally, environmental enrichment has been hypothesized to improve the cognitive ability in neuropathic diseases, and Tip60 may mediate these beneficial effects [ 29 ].…”