NEUROTROPHIC SUPPORT IN AGING AND ALZHEIMERS DISEASE

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DESCRIPTION: (Applicant's abstract) Basic fibroblast growth factor (FGF2) is a potent mitogen and neurotrophic factor. The mature CNS contains a surprisingly high level of this factor. FGF2 lacks a hydrophobic signal peptide sequence and is not efficiently released from unstimulated healthy cells. It is our hypothesis that injury causes the release of FGF2, resulting in the activation of widely expressed transmembrane FGF receptors (FGFRs). This hypothesis suggests that the main role of FGF2 within the nervous system is to serve as an early signal of cell injury and to initiate injury responses, including glial activation and neuronal plasticity. The following specific aims will test this proposed physiological model of FGF2 action: Aim 1: To test whether injury releases FGF2 into the extracellular space and activates FGF receptors. The levels of extracellular FGF2 in normal and injured CNS will be quantified in vivo using a highly sensitive FGF2 assay. FGF-receptor activation after injury will be also be measured. Aim 2: To test whether simple plasma membrane breach or additional specific export mechanisms cause the release of FGF2 after injury. FGF2 release mechanisms will be characterized in astrocyte cultures. Aim 3: To test whether the hippocampal cytoarchitecture of FGF2 knockout and FGF2 over-expressing transgenic mice is normal, but that injury responses are altered. Immunohistochemical analysis employing appropriate markers will be used to determine the effect of FGF2 absence or overexpression on neuronal survival, axonal sprouting and glial reactivity in normal and injured mouse hippocampus. Aim 4: To test whether FGF2 regulates the expression of proteins that are involved in promoting plasticity and repair. The effect of FGF2 knockout and over-expression on the levels of neurotrophins, cytokines and chemokines will be determined. Aim 5: To test whether FGF2 is important in the normal maintenance of the aging CNS. The volume of hippocampus, neuronal and glial numbers, and cytoarchitecture of hippocampus of old FGF2 knockout and FGF-2 overexpressing mice will be determined.