The proposed research project seeks to improve our understanding of the development, maintenance of function, and degeneration of brain cholinergic neurons which degenerate in Alzheimer's disease. A greater understanding of the mechanisms involved in neuronal degeneration and the means to enhance the regenerative ability of brain neurons would lead to novel strategies for the therapy of Alzheimer's disease. Neurodegenerative diseases may be caused in part by a deficiency of specific neurotrophic factors that are required for the development and maintenance of brain neurons.
The specific aim of the project is the purification and characterization of a novel membrane-associated neurotrophic factor specific for central nervous system cholinergic neurons. The hippocampus and cortex are the innervation areas for the basal forebrain cholinergic neurons. Hippocampal neurons and membranes prepared from the hippocampus stimulate the expression of cholinergic properties of these neurons maintained in primary cell culture. Protein separation methods, including hydrophobic interaction chromatography, ion-exchange chromatography, gel filtration chromatography, isoelectric focusing, and high performance liquid chromatography will be used to purify the neurotrophic protein present in hippocampal membrane extracts. Antibodies prepared against the factor will elucidate the normal tissue and cellular distribution of the factor as well as the regulation of the cholinergic neurotrophic factor in experimental models of neurodegenerative diseases. An extensive characterization of the effects of the trophic factor on the expression of cholinergic properties in primary cultures of basal forebrain neurons with comparison to effects on other cell types will delineate the specificity of activity. Potential interactions between the purified brain membrane-associated factor and other known neurotrophic factors, such as nerve growth factor, will be investigated.
