Current lab interests include identifying the underlying mechanisms through which individual components of peripheral metabolic dysregulation (particularly hyperinsulinemia and hypercholesterolemia) impact brain function. We focus on physiological and calcium imaging techniques to identify neuronal changes with age. Ca2+-sensitive biomarkers known to be modified in aging in the hippocampus include single L-type voltage-gated Calcium channels, the Ca2+-dependent AHP, and Ca2+ transients.
We use these and other molecular techniques in models of aging (F344 rat) and in primary hippocampal neurons (cell attached patch clamp recordings) to also identify signaling pathways and mechanisms that may be altered with aging. Some studies monitor Ca2+-induced Ca2+ release functions with aging.
Another important facet of our work is to understand the impact of thiazolidinediones (TZDs) in the brain. TZDs are primarily used to reestablish insulin sensitivity and reduce glucose levels in type 2 diabetics but recently, new results have shown improved cognition in AD patients taking TZDs. These compounds are PPAR-Gamma agonists and have multiple actions in neurons and astrocytes (Pancani et al., 2009). We are particularly interested in their actions at voltage-gated calcium channels and in regulating glucose utilization (Pancani et al., 2011).
A third emphasis has focused on developing a new technique for measuring bioenergetics with sufficient spatial and temporal resolution for analysis in single live cells. We have been using a new and alternative method for measuring glucose utilization in single live cells (2-NBDG). Rather than measuring the uptake of a fluorescent glucose analog, this imaging technique uses disappearance of the indicator as evidence of utilization.
We are currently using intranasal insulin delivery to try to offset cognitive decline in aged F344 animals and also investigating the use of skin fibroblasts as baseline predictors of responses to antidiabetic treatment. We will be implimenting the use of a new glucose nanosensor to studies of brain aging soon.
Our combined efforts, including behavioral and microarray approaches are aimed at identifying novel therapeutic targets that may contribute to prevention of cognitive decline with aging and/or Alzheimer's disease (AD).