The neurodegenerative diseases - Amyotrophic Lateral Sclerosis (ALS), Parkinson's disease, and Alzheimer's disease - are devastating clinical disorders that result in selective neuronal injury and death. Our general hypothesis is that increased intracellular calcium, and limited calcium buffering capacity, may be critically important in neurodegenerative cell injury. Our specific studies in ALS have documented the presence of antibodies to voltage-gated calcium channels (VGCC), which lead to increased intracellular calcium and cytotoxicity in vitro; and our studies in Alzheimer's disease have documented that beta amyloid peptide also increases intracellular calcium, albeit by a different mechanism, leading to cytoxicity in vitro. ALS IgG enhance calcium current of different neuronal VGCC (e.g. P-type channels in Purkinje cells and lipid bilayers; N-type channels in Xenopus oocytes expressing rat brain VGCC; and P-type or Q-type channels in a motor neuron cell line [VSC 4.1]). In VSC 4.1, the ALS IgG-mediated increase in calcium current leads to increased intracellular calcium and to cell death. This cell system as well as Xenopus oocytes injected with VGCC and rat brain mRNA will allow us to use calcium imaging and electrophysiological techniques to characterize the effects of ALS IgG on different VGCC and on calcium homeostasis and to examine the contribution to cytotoxicity of second messenger systems, including G proteins, protein kinases and phosphatases, and the calcium binding proteins calbindin D28K and parvalbumin. Factors mediating selective vulnerability in sporadic Alzheimer's disease are not well defined. Our recent studies document that beta amyloid leads to increased intracellular calcium and cell death of a substantia nigra cell line. Removal of extracellular calcium attenuates cytotoxicity, but VGCC antagonists have not effect. Aurintricarboxylic acid, an inhibitor of apoptosis, completely blocks cell death. This cell system will permit us to employ the same calcium imaging, electrophysiological and pharmacological techniques to define how beta amyloid leads to increased intracellular calcium, and to determine the role of increased intracellular calcium in mediating beta amyloid-induced cytoxicity and the influence of calcium binding proteins, calbindin D28K and/or parvalbumin on cell injury. Such studies should provide insight into the roles played by increasing intracellular calcium and altered calcium buffering on selective neuronal vulnerability in sporadic neurodegenerative disorders.

National Institute of Health (NIH)
National Institute on Aging (NIA)
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Doody, R; Pavlik, V; Massman, Paul et al. (2005) Changing patient characteristics and survival experience in an Alzheimer's center patient cohort. Dement Geriatr Cogn Disord 20:198-208
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Davis, Robert N; Massman, Paul J; Doody, Rachelle S (2003) Effects of blood pressure on neuropsychological functioning in Alzheimer's disease. Arch Clin Neuropsychol 18:19-32

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