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J. Biol. Chem., Vol. 276, Issue 4, 2523-2530, January 26, 2001

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The Role of G Protein Activation in the Toxicity of Amyloidogenic A-(1-40), A-(25-35), and Bovine Calcitonin^*

Dawn L. Rymer and Theresa A. Good

From the Department of Chemical Engineering, Texas A & M University, College Station, Texas 77843-3122

More than 16 different proteins have been identified as amyloid in clinical diseases; among these, -amyloid (A) of Alzheimer's disease is the best characterized. In the present study, we performed experiments with A and calcitonin, another amyloid-forming peptide, to examine the role of G protein activation in amyloid toxicity. We demonstrated that the peptides, when prepared under conditions that promoted -sheet and amyloid fibril (or protofibril) formation, increased high affinity GTPase activity, but the nonamyloidogenic peptides had no discernible effects on GTP hydrolysis. These increases in GTPase activity were correlated to toxicity. In addition, G protein inhibitors significantly reduced the toxic effects of the amyloidogenic A and calcitonin peptides. Our results further indicated that the amyloidogenic peptides significantly increased GTPase activity of purified G_o and G_i subunits and that the effect was not receptor-mediated. Collectively, these results imply that the amyloidogenic structure, regardless of the actual peptide or protein sequence, may be sufficient to cause toxicity and that toxicity is mediated, at least partially, through G protein activation. Our abilities to manipulate G protein activity may lead to novel treatments for Alzheimer's disease and the other amyloidoses.

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