NEUROTROPHIC SUPPORT IN AGING & ALZHEIMER'S DISEASE

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The mechanisms regulating development and maintenace of the complex and specific innervation patterns characteristic for mammalian central nervous system remain poorly understood. Seveal independent observations, however, suggest that two different types of specific extracellular molecular signals play a major role in this process. The first type of signal are soluble neurotrophic factors that support the survival and differentiation of specific types of neurons, and the second type of signal is thought to consist of insoluble molecules that provide areas of selective adhesion to growing neurites. Identification and characterization of such molecular signals, as well as knowing how the expression of these molecules is regulated, are of central important for understanding of how innervation patterns develop and are maintained. It is of special interest to identify the role of such molecules in aging and to investigate whether interference with their action is involved in the etiology of neurodegenerative disorders, such as Alzheimer's disease (AD). This proposal describes a study focused on the identification of the cell types and molecules providing trophic signals to the cholinergic neurons in basal forebrain that innervate hippocampus and cerebral cortex. It will also be studied how the expression of neurotrophic support is regulated and what the role of such support in aging and AD. Previously, in collaboration with others, I have shown that Nerve Growth Factor (NGF) promotes differentiation in cholinergic basal forebrain neurons. Preliminary results suggest that NGF alone can not completely replace the trophic support derived from glial cells. In addition, I have recently obtained several monoclonal antibodies to antigens induced in specific classes of glial cells during injury-induced sprouting of the cholinergic innervation of hippocampus. The goals of this study are: - To determine what molecules support the survival and differentiation of cholinergic basal forebrain neurons. - To identify the cell type that produces such molecules. - To characterize whether specific classes of glial cells express additional trophic support when expressing the injury-induced antigens. - To study the molecular properties of the injury-induced antigens. - To investigate the levels and the regulation of expression of trophic support and the injury-induced antigens in aging and degenerative disease. Methods to be used include growing basal forebrain neurons in culture in the presence of known neurotrophic factors and tissue extracts; co-culturing of basal forebrain neurons with different types of feeder-layers and feeder-layer derived molecules; and biochemical and immunochemical characterization and purification of relevant molecules.