Progressive neuronal degeneration underlies the cognitive dysfunction of Alzheimer's disease (AD). The neuritic plaque, consisting of deposits of Beta-amyloid (BetaA4) protein surrounded by reactive glia and degenerating neurons, is a hallmark of AD. Given the role of astrocytes (glial cells) in regulating the development and viability of neurons, the goal of this project is to test the hypothesis that abnormal glial-neuronal interactions influence neurodegeneration by altering neuronal Ca2+ homeostasis. One series of experiments will utilize the trisomy 16 (Ts16) mouse which contains an extra copy of chromosome 16, on which is located the gene coding for Beta-amyloid precursor protein (BetaAPP) and the mouse homolog of the putative familial AD locus. In order to test whether increased expression of one or more chromosome 16 genes affects neuronal properties, the effects of astrocytes and astrocyte-derived substances on the viability and structure of hippocampal neurons will be studied in vitro by co- culturing various combinations of Ts16 and euploid neurons and astrocytes, by examining effects of Ts16 and euploid astrocyte-conditioned medium on neuronal properties, and by adding various putative glial-derived growth factors and their neutralizing antibodies to the neuronal cultures. The role of intracellular Ca2+ in the premature death of Ts16 neurons in culture will be examined by computer-assisted imaging of ionized internal Ca2+ levels in Ts16 and euploid neurons using the fluorescent Ca2+ indicator, fura-2. A second series of experiments will study S100Beta, a Ca2+-binding protein widely distributed in brain in man, that is elevated in AD. S100Beta has been reported to have both neurotrophic and glial mitogenic activity. In order to test the hypothesis that excessive levels of S100Beta may overstimulate neuronal process formation, making the neuron more vulnerable to a loss of intracellular Ca2+ regulation, cultured hippocampal neurons from normal mice will be studied in the presence of S100Beta or anti-S100Beta antibodies. Neuronal viability and neurite configuration will be evaluated. The effects of S100Beta overexpression on astrocyte structure, function, and development will be investigated in cultured hippocampal astrocytes from transgenic S100Beta mice and in sections of transgenic S100Beta mouse brain. In addition, regulation of neuronal and astrocyte intracellular CA2+ in the presence of S100Beta will be studied by imaging of fura-2 fluorescence.
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