Epigenetics of the Aging Astrocyte: Implications for stroke

Project Abstract: Menopause increases the risk and severity of ischemic stroke and the subsequent risk for dementia. Clinical and experimental studies indicate that the loss of estrogen contributes to elevated risk for both diseases. However, the landmark Women's Health Initiative study showed that menopause hormone therapy increased stroke-related mortality and the risk for dementia. Our studies have shown that ischemic stroke outcomes are worse in middle-aged, reproductive senescent (acyclic) female rats, as compared to younger, normally cycling female rats. Moreover, estrogen replacement to the acyclic group exacerbates stroke outcomes. Our recent studies show that the events during the acute period of ischemic stroke progress to chronic impairment in cognition and depression, key components of a dementia-like phenotype. In the initial funding period, we identified epigenetic changes in the aging astrocyte resulting from stroke in reproductive senescent females. In the previous (just completed) funding period, we focused on mir20a-3p, a member of the epigenetically modified mir17-92 cluster. Mir20a-3p shows a remarkable age-specific regulation in the acute phase of stroke, namely profound elevation in adult female astrocytes, but downregulation in middle-aged female astrocytes. Intravenous (IV) mir20a-3p treatment to middle-aged females after stroke reduced infarction and sensorimotor impairment in the acute phase and attenuated cognitive impairment in the chronic phase, indicating a role for this microRNA in stroke neuroprotection. Cognitive impairment in our model was seen in several domains including associative learning, episodic memory and spatial learning and recall. These impairments are abrogated with mir20a-3p treatment, and thus offer a unique opportunity to understand the pathophysiology of stroke-induced cognitive deficits. This competitive renewal application will focus on the mechanisms of stroke-induced cognitive impairment by testing the hypothesis that stroke causes a sustained modification of microglial phenotypes resulting in secondary neurodegeneration in forebrain cognitive circuits, which is attenuated by astrocytic mir20a-3p. This proposal will therefore focus on the interactions between astrocytes and microglia, and specifically the putative mir20a-3p target gene interleukin (IL)-17A. In three aims we will test (1) whether Il-17A, an inflammatory cytokine, promotes cognitive impairment, by manipulating both the cytokine as well as its receptor, (2) using `omic' approaches to determine whether stroke causes a persistent phenotypic and functional change in microglia associated with secondary neurodegeneration, and if these changes are prevented by mir20a-3p, and finally (3) to test the impact of endocrine signaling by mir20a-3p in middle-aged astrocytes on stroke-induced cognitive impairment. Using translationally relevant stroke models, multiple outcome measures and gene transfer tools, this application will critically evaluate the pathophysiology underlying the progression of acute stroke deficits to chronic stroke outcomes, which is understudied in aging females.