SUMMARYThe overall goal of the proposed studies is to test the hypothesis that type 2 diabetes (T2D)-induced epigeneticchanges in the brain may contribute to cognitive decline by altering the expression of mitochondrial andsynaptic genes, resulting in cellular energy metabolism dysregulation and neuronal and dendritic spinestructure/activity impairments, ultimately leading to cognitive dysfunction. It is known that diabetes is a riskfactor for dementia. However, the underlying mechanisms linking T2D and cognitive decline are largelyunknown. Emerging evidence has demonstrated that T2D-associated chromatin modifications pertinent toepigenetic mechanisms play an important role in the pathogenesis of diabetes. We found significantupregulation in the expression of select chromatin modification enzymes, histone deacetylases (HDACs) classIIa in the brains of T2D subjects compared to non-T2D control subjects, and found that these changes coincidewith 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 energymetabolism, synaptic plasticity, and spatial memory function. Treatment with an HDAC class IIa specificinhibitor can effectively restore synaptic plasticity in hippocampal slices isolated from these T2D mice, andimproves 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, wepropose to systematically and mechanistically investigate, both in vitro using primary neurons and in vivo usinga mouse model of diabetes, how diabetes-mediated epigenetic changes may affect molecular and cellularpathways that lead to dysregulation of energy metabolism, impairments in synaptic plasticity, and cognitivedysfunction. Our proposed studies will clarify the role of HDAC IIa in diabetes-mediated cognitive impairmentand provide novel therapeutic targets for prevention or treatment of cognitive dysfunction in the context of T2D.
|Effective start/end date||1/07/17 → 30/06/21|
- U.S. Department of Veterans Affairs: $298,463.00