Fibrillar Alzheimer's amyloid peptide Abeta(1-42) stimulates low density lipoprotein binding and cell association, free radical production and cell cytotoxicity in PC12 cells.
Amyloid forming peptides are known to disturb vital cellular functions and induce cell death. However, the mechanisms by which fibrillogenic peptides induce cytotoxic effects in various cells has not been established. In this study the effects on low density lipoprotein binding and uptake of fibrils of the Alzheimer's amyloid beta-peptide (Abeta(1-42)), which is known to play a central role in the pathogenesis of Alzheimer's disease, were investigated in pheochromocytoma PC12 cells. Fibrillar Abeta(1-42) at micromol concentrations increased low-density lipoprotein (LDL) binding and cell association by 460% and 200% respectively, and LDL degradation by about 62%. Approximately 49% and 34% of Abeta fibril stimulated LDL cell association and degradation was inhibited by anti-LDL receptor antibodies. The soluble form of Abeta had no effect on any of these measures of LDL metabolism. The observed increased glutathione reductase activity, DNA fragmentation (TUNEL assay) and decreased DNA synthesis ([(3)H] thymidine incorporation assay) in cells treated with Abeta(1-42) fibrils alone or together with LDL relative to controls, suggests that the interaction of fibrils with LDL receptors might be one possible pathway which contributes to fibril cytotoxicity.
Janciauskiene
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Gastroenterology-Hepatology Division, Department of Medicine, University Hospital, Malmö, Sweden. sabina.janciauskiene@medforsk.mas.lu.se
Wright
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HT
Lindgren
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D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D008078:Cholesterol, LDL / Q000378:metabolism*; D003603:Cytotoxins / Q000494:pharmacology; D005609:Free Radicals / Q000378:metabolism; D005980:Glutathione Reductase / Q000378:metabolism; D007457:Iodine Radioisotopes; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D010084:Oxidation-Reduction; D016716:PC12 Cells; D010446:Peptide Fragments / Q000633:toxicity*; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D013936:Thymidine / Q000378:metabolism / Q000494:pharmacology; D014316:Tritium
D016229:Amyloid beta-Peptides; D008078:Cholesterol, LDL; D003603:Cytotoxins; D005609:Free Radicals; D007457:Iodine Radioisotopes; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D014316:Tritium; D005980:Glutathione Reductase; D013936:Thymidine