SUMMARY The overall goal of the proposed studies is to test the hypothesis that type 2 diabetes (T2D)-induced epigenetic changes in the brain may contribute to cognitive decline by altering the expression of mitochondrial and synaptic genes, resulting in cellular energy metabolism dysregulation and neuronal and dendritic spine structure/activity impairments, ultimately leading to cognitive dysfunction. It is known that diabetes is a risk factor for dementia. However, the underlying mechanisms linking T2D and cognitive decline are largely unknown. Emerging evidence has demonstrated that T2D-associated chromatin modifications pertinent to epigenetic mechanisms play an important role in the pathogenesis of diabetes. We found significant upregulation in the expression of select chromatin modification enzymes, histone deacetylases (HDACs) class IIa in the brains of T2D subjects compared to non-T2D control subjects, and found that these changes coincide with altered expression of proteins involved in synaptic function. Using an experimental mouse model of T2D, we found similar epigenetic changes in the brains, and the mice also exhibited impairments in energy metabolism, synaptic plasticity, and spatial memory function. Treatment with an HDAC class IIa specific inhibitor can effectively restore synaptic plasticity in hippocampal slices isolated from these T2D mice, and improves energy metabolism in vitro, indicating that HDAC class IIa might play an important role in T2D- induced energy metabolism dysregulation and synaptic impairments in the brain. Based on this evidence, we propose to systematically and mechanistically investigate, both in vitro using primary neurons and in vivo using a mouse model of diabetes, how diabetes-mediated epigenetic changes may affect molecular and cellular pathways that lead to dysregulation of energy metabolism, impairments in synaptic plasticity, and cognitive dysfunction. Our proposed studies will clarify the role of HDAC IIa in diabetes-mediated cognitive impairment and provide novel therapeutic targets for prevention or treatment of cognitive dysfunction in the context of T2D.

NARRATIVE Nearly one in four veterans receiving care from the Veterans Health Administration (VHA) has Type 2 diabetes mellitus (T2D) and the incidence continues to rise every year. T2D is strongly associated with the onset and progression of cognitive deterioration. T2D is one of the potentially modifiable risk factors for cognitive dysfunction including dementia. Our study demonstrated that T2D-mediated epigenetic changes in the brain may causally induce pathophysiological changes that eventually contribute to impairments in energy metabolism and synaptic function, which are the essential components of brain integrity and intact cognitive function. Given the foreseeable increased need for dementia treatment in the coming years, understanding the molecular mechanisms underlying the epigenetic changes as a result of T2D conditions may influence cognitive function in the aging brain will provide invaluable insight for developing immediate novel therapeutic interventions to prevent or delay T2D-mediated cognitive dysfunction in the aging veteran population.