Acidic and basic fibroblast growth factors (FGFs) are polypeptides with potent multipotential trophic effects on central nervous system (CNS) cells: They are potent gliotrophic factors that promote the survival and proliferation of CNS glia. They are angiogenic factors that promote capillary growth and proliferation. They are potent neuronotrophic factors that promote the survival and outgrowth of a variety of CNS neurons. Recent evidence indicates that FGFs play an important role in the development, plasticity, and repair of the mammalian brain. In previous studies, we have developed methods for the assay of FGFs and their mRNA's, and for the immunolocalization of FGFs in brain. These studies have shown large changes in FGF expression during brain development and following focal injury or stroke. The proposed studies will examine the role of FGFs in the aging brain, and will test the specific hypotheses that the expression, receptors, and in vitro effects of FGFs diminish with aging. Such changes may have profound consequences on cell survival, plasticity, and repair in the aging brain. Heparin-affinity HPLC bioassay and immunoassay techniques will be used to determine changes in the relative levels of aFGF and bFGF in the aging rodent brain. Northern blotting and in situ hybridization techniques will be used to determine changes in the levels and cellular localization of FGF mRNA's. Immunohistochemical and in situ autoradiographic techniques will be used to determine changes in the relative density and cellular localization of FGF receptors. We will also directly test the in vivo cellular effects of FGFs on the mature and aging brain. Finally, we will follow-up on preliminary studies showing striking changes in FGF immunoreactivity in post-mortem human brain with Alzheimer Disease (AD). These studies will provide novel information concerning the role of FGFs in the aging brain, and may have important therapeutic implications for aging and AD.
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