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.
Highlights
Alzheimer’s disease (AD) is the most common form of dementia in the aging population and its progression is tightly associated with cognitive impairments that involve learning and memory deficits
Using a well-established social EE paradigm in Drosophila we show that EE conditions induce significant beneficial structural changes that include axonal outgrowth in the mushroom body (MB) of control w1118 flies when compared to their genetically identical siblings housed in isolated (ISO) conditions
We find that loss or gain of Tip60 histone acetyltransferases (HATs) levels in the MB results in a loss of this beneficial EE mediated MB axonal outgrowth response, indicating that appropriate levels of Tip60 are required for EE neuroadaptative structural MB benefits
Summary
Alzheimer’s disease (AD) is the most common form of dementia in the aging population and its progression is tightly associated with cognitive impairments that involve learning and memory deficits. The pathology of AD has been linked to neuronal cell death and disrupted synaptic plasticity in various brain regions that include the hippocampus and the cortex. Increasing compelling evidence demonstrates that AD progression is influenced by a complex interplay between genetic and environmental risk factors, and that such gene-environmental interactions play a major role in triggering pathways that can either slow or exacerbate disease progression. Environmental stimuli provide neurons in the brain with instructive information that shapes synaptic connections to impact cognitive ability. Environmental enrichment (EE) conditions have beneficial effects for reinstating cognitive ability in neuropathologi-.
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