Amyloid peptides are toxic via a common oxidative mechanism.
beta-Amyloid protein (A beta) is a member of a small group of proteins that accumulate as amyloid deposits in various tissues. It has recently been demonstrated that the toxicity of A beta toward some neural cells is caused by oxidative damage. Since all of the amyloid diseases are characterized by protein deposited in the antiparallel beta-sheet conformation, it was asked whether there is a common toxic mechanism. It is shown here that the protein components of other human amyloidoses, including amylin, calcitonin, and atrial natriuretic peptide, are all toxic to clonal and primary cells. The toxicity is mediated via a free radical pathway indistinguishable from that of A beta. Experiments with synthetic peptides suggest that it is the amphiphilic nature of the peptides generated by their beta structure rather than their beta structure per se that causes toxicity. These results tend to rule out the alternative that amyloid toxicity is exclusively mediated via specific cell surface receptors.
Schubert
D
D
Salk Institute for Biological Studies, San Diego, CA 92186-5800.
Behl
C
C
Lesley
R
R
Brack
A
A
Dargusch
R
R
Sagara
Y
Y
Kimura
H
H
D000595:Amino Acid Sequence; D000682:Amyloid / Q000494:pharmacology; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity*; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000494:pharmacology; D001932:Brain Neoplasms; D002116:Calcitonin / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D005434:Flow Cytometry; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins; D058228:Islet Amyloid Polypeptide; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D008555:Melitten / Q000494:pharmacology; D008969:Molecular Sequence Data; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology; D009861:Onium Compounds / Q000494:pharmacology; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity*; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D017433:Protein Structure, Secondary; D051381:Rats; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D014862:Wasp Venoms / Q000494:pharmacology; D003189:p-Methoxy-N-methylphenethylamine / Q000494:pharmacology
D000682:Amyloid; D016229:Amyloid beta-Peptides; D036341:Intercellular Signaling Peptides and Proteins; D058228:Islet Amyloid Polypeptide; D009842:Oligopeptides; D009861:Onium Compounds; D010446:Peptide Fragments; D010455:Peptides; D014862:Wasp Venoms; C074636:amyloid beta-protein (25-35); D008555:Melitten; D003189:p-Methoxy-N-methylphenethylamine; C007517:diphenyleneiodonium; C037500:mastoparan; D009320:Atrial Natriuretic Factor; D002116:Calcitonin; D006861:Hydrogen Peroxide; D007770:L-Lactate Dehydrogenase; D009247:NADH, NADPH Oxidoreductases