| Regarding age-related decline in memory performance, we have focused on the cholinergic and glutamatergic systems and their interaction. For cholinergic interventions, we have collaborated with Dr. Nigel Greig of the Laboratory of Neurosciences to develop a novel class of cholinesterase inhibitors, that are long-acting, highly specific for acetylcholinesterase, with a wide range of therapeutic efficacy and low toxicity within this range. For glutamatergic interventions, we are examining manipulations of the glycine and polyamine sites on the N-methyl-D-aspartate (NMDA) glutamate receptor as well as generators of nitric oxide (NO) that is activated through the NMDA receptor. We have found that combinations of glycine agonists and polyamine agonists can act synergistically to improve learning performance. NO donors are also being assessed to overcome age-related learning impairments. Collaborating with Dr. Peter Mouton, we are examining the role of estrogen in preserving memory and reducing glia-mediated inflammation in a mouse model of Alzheimer's disease. In addition to the behavioral analysis, the latter project is part of a larger collaboration with Drs. Peter Mouton and Mathias Jucker that involves quantitative morphometrics using unbiased stereology in a variety of mouse models. Specifically, we are assessing age-related changes in the numbers of neurons, synapses, and glia, in the hippocampus of mice from different genders and strains including transgenics and knock-outs. The objective is to relate specific neuromorphometric parameters to age or treatment-induced changes in cognitive performance. In collaboration with Drs. Nan-Ping Weng and Dan L. Longo of the Laboratory of Immunology, we are using microarray technology to identify genes involved in memory formation and possible age-related changes in gene expression. Several candidate genes have been identified that show little expression in the hippocampus of learning-impaired rats compared to higher levels of expression in young rats. |
