Translational Research on Alzheimer’s Disease (AD) AD is by far the most prevalent neurodegenerative disease of aging. It is characterized by complex relationships between multiple interrelating biological and pathologic phenotypes. Major contributory pathologic factors to AD include aberrantly aggregated oliogmeric beta-amlyoid (oAβ), hyperphosphorylated tau proteins, and glia-mediated neuroinflammation. There is no cure for AD and available treatments are only symptomatic and do not change the progressive course of the disease. It is currently thought that the lackluster performance of preclinical paradigms and concepts for developing AD therapies might be due to the inadequacy of the prevailing approach of targeting single mechanisms instead of multiple AD mechanisms. Our research focuses on identifying bioactive agents that can simultaneously interfere with these pathologic mechanisms as novel strategies for the prevention and therapeutic treatment of AD.

Translational Research on Major Depressive Disorder (MDD) Stress-mediated synaptic maladaptation in the nucleus accumbens (NAc) and induction of inflammatory cytokines in the periphery contribute to depression-like behaviors both in humans and in experimental models. Both peripheral inflammation and synaptic plasticity maladaptation have emerged as newly hypothesized clinical intervention targets for depression. Our research focuses on identifying bioactive agents that can normalize synaptic plasticity in the NAc and/or inhibit stress-induced peripheral inflammation as novel therapeutic strategies for the treatment of depression. Our approach is particularly important for depression patients who are resistant to current antidepressant treatment, and especially those who suffer from chronic depression and are characterized by high plasma levels of inflammatory cytokines.

The Influence of Life Style on Cognitive Function It is well known that diabetes is a risk factor for dementia. However, the underlying mechanisms linking type II diabetes (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 and improves energy metabolism, indicating that HDAC class IIa plays an important role in T2D-induced energy metabolism dysregulation and synaptic impairments in the brain. Our current investigation dissects the mechanisms underlying T2D-mediated HDAC IIa upregulation and associated metabolic and synaptic alteration and tests whether changes in lifestyle including diet, physical exercise, and pharmacological intervention targeting HDAC IIa may beneficially preserve or improve cognitive function in the context of T2D.