The role of G protein activation in the toxicity of amyloidogenic Abeta-(1-40), Abeta-(25-35), and bovine calcitonin.
More than 16 different proteins have been identified as amyloid in clinical diseases; among these, beta-amyloid (Abeta) of Alzheimer's disease is the best characterized. In the present study, we performed experiments with Abeta 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 beta-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 Abeta and calcitonin peptides. Our results further indicated that the amyloidogenic peptides significantly increased GTPase activity of purified Galpha(o) and Galpha(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.
Rymer
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Department of Chemical Engineering, Texas A & M University, College Station 77843-3122, USA.
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D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000633:toxicity*; D000686:Amyloidosis / Q000209:etiology; D000818:Animals; D002116:Calcitonin / Q000737:chemistry / Q000633:toxicity*; D002417:Cattle; D002462:Cell Membrane / Q000378:metabolism; D004789:Enzyme Activation; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology; D009498:Neurotoxins / Q000037:antagonists & inhibitors; D016716:PC12 Cells; D010446:Peptide Fragments / Q000737:chemistry / Q000633:toxicity*; D011485:Protein Binding; D017433:Protein Structure, Secondary; D051381:Rats
D016229:Amyloid beta-Peptides; D018696:Neuroprotective Agents; D009498:Neurotoxins; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C113041:amyloid beta-protein (35-25); D002116:Calcitonin; D019204:GTP-Binding Proteins