Our laboratory is investigating the mechanism of memory disruption and synaptic dysfunction in Alzheimer’s Disease. We use a combination of cell culture and transgenic animal approaches in an attempt to understand why the overexpression of the amyloid precursor protein (APP) or direct application of its active peptide, A-beta, inhibits intracellular signaling in neuronal cells and leads to alterations of electrical activity, dendritic spine morphology and behavior.  These results are extended with analyses of neurons taken from post-mortem Alzheimer’s Disease brains. In the past two years our attention has been on the PKA-CREB signaling pathway and on the role of ubiquitin c-terminal hydrolase-L1 (Uch-L1) in regulating these events. We have used both drugs and protein transduction techniques to show that A-beta induced changes, both in culture and in the animal, can be reversed by restoring these pathways to their normal “balance”. Other projects involve the induction of  neurogenesis in neural stem cells by A-beta raising the possibility of an endogenous repair mechanism in AD, and the analysis of the action of the ginkgolides on neuronal function. The laboratory approaches these questions with a wide range of tools including biochemistry, cell biology, physiology and microscopy.