Research in my lab is broadly focused on Alzheimer’s disease (AD), with the general goals of elucidating factors that regulate AD pathogenesis and pursuing translational approaches that will be useful in the prevention and/or treatment of the disease. Our approach to investigating research questions involves the use of complementary cellular, biochemical and molecular techniques to analyze relationships in human tissues, wild-type and transgenic rodent models, and cultured cells.

A primary area of focus in my laboratory is the relationship between age-related loss of steroid hormones and the development of AD. For example, our research with postmortem human brain has helped to identify testosterone loss in aging men as a risk factor for AD. In rodent models, we observe that depletion of androgens accelerates development of AD-like neuropathology and increases neuronal vulnerability to toxic insult. Cell culture studies continue to identify the relevant underlying mechanisms for these androgen effects, including investigation of classic genomic actions (e.g., regulation of genes such as neprilysin) as well as activation of rapid cell signaling pathways (e.g., MAPK/ERK, CREB, PKC). In ongoing translational studies, we are building upon our basic science advances to develop specific therapeutic interventions that selectively activate protective androgen pathways (e.g., synthetic testosterone mimetics). Using this general research strategy, we are pursuing conceptually parallel basic science and translational projects to evaluate the interactions between estrogen and progesterone actions in the regulation of neurodegenerative cascades associated with AD.

A new area of research in the lab seeks to understand the relationships between obesity, type 2 diabetes, and AD. Recent epidemiological findings have identified obesity in middle age, and its downstream consequences metabolic syndrome and type 2 diabetes, as significant risk factors for the development of AD in old age. Our efforts are focused at understanding the mechanistic links between these conditions, including the interactive roles of adiposity, neuroinflammation, and age-related changes in testosterone and estrogen.