The research activities in our lab are focused on two closely related areas, age-dependent changes in brain that underlie vulnerability to neurodegenerative diseases, and development of novel therapeutics to help slow the progression of Alzheimer disease (AD) and related protein- misfolding diseases. Calcium signaling is a critical determinant of neuronal function and the final pathway allowing for cell survival or triggering cell death. Subtle alterations in calcium regulation as the brain ages are well-documented in many experimental paradigms, though the underlying mechanisms are not yet known. We have found that the activity of the critical plasma membrane calcium pump (Ca2+-ATPase) is markedly reduced in aging brain and that this reduction may be due to the oxidative stress that increases with age. Our ongoing studies on calcium regulation are carried out both in brain tissue from aging animals and in brain neurons grown in cell culture. The approaches used in these studies include biochemical assays, proteomics analyses, gene-manipulations via siRNA, and mass spectrometric assessment of membrane lipid changes that affect calcium transporting proteins.
Dysregulation in calcium handling may contribute to the age-dependent increase in vulnerability to neurodegenerative diseases such as AD. The second component of our research program is devoted to assessing the actions of drugs that may protect neurons from the cell death induced by the amyloid peptides involved in AD. We use primary neurons in culture to identify drugs targeted to specific pathological pathways and determine if they protect neurons against the amyloid peptide toxicity. The drugs are synthesized by faculty in Medicinal Chemistry, and they are then evaluated by Pharmaceutical Chemistry faculty for permeability into the brain. The permeable agents are then further characterized for potential in vivo proof of concept experiments in mouse models of AD. This project involves extensive interdisciplinary collaborations with faculty in other departments, including a neuropathologist from the KU Medical Center. The permeable agents are then examined in relevant AD mouse models in our lab through a combination of biochemical, immunocytochemical, neuropathological, and cognitive performance assays. This multidisciplinary strategy is very beneficial for all of the lab trainees, and it has been quite fruitful in enabling us to develop very promising novel compounds that may help slow progression of age-dependent neurodegenerative diseases.