Acidic pH promotes the formation of toxic fibrils from beta-amyloid peptide.
Beta-amyloid (Abeta) peptides, the major component of senile plaques in brains of patients with Alzheimer's disease (AD), were found in the low pH organelles (i.e. endosome/lysosome) of cultured neuronal cells. Since acidic pH values have been shown to promote the self-assembly of Abetas, which seems to be a prerequisite for their neuropathogenicity, elucidating the aggregation behavior of Abetas in acidic environments and their subsequent effects on neuronal cells may be crucial for understanding the neurodegenerative process of AD. In this study, the extent and rate of aggregation of Abeta(1-42) peptides at pH values of 5.8 and 7.4, as well as the structure and neurotoxic effects of these aggregates, were examined. We showed that Abeta(1-42) peptides formed large and complex fibrils much more efficiently at acidic rather than neutral pH. Furthermore, only the pH 5.8 Abeta aggregates induced significant apoptotic death of PC12 cells, as indicated by a decrease in 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium bromide (MTT) reduction and an increase in phosphatidylserine externalization. Taken together, our results suggest that the Abetas present in the acidic organelles may form neurotoxic fibrils more easily than those in the neutral cellular compartments.
Institute of Biopharmaceutical Science, College of Life Science, National Yang-Ming University, Shih-Pai, Taipei 11221, Taiwan, ROC. yeusu@ym.edu.tw
Y
Y
Su
P T
PT
Chang
D000143:Acids / Q000737:chemistry*; D000682:Amyloid / Q000138:chemical synthesis* / Q000633:toxicity; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D002470:Cell Survival / Q000187:drug effects; D005456:Fluorescent Dyes; D006863:Hydrogen-Ion Concentration; D046911:Macromolecular Substances; D008856:Microscopy, Fluorescence; D016716:PC12 Cells / Q000187:drug effects / Q000473:pathology; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism*; D010718:Phosphatidylserines / Q000096:biosynthesis; D051381:Rats; D013778:Tetrazolium Salts; D013844:Thiazoles
D000143:Acids; D000682:Amyloid; D016229:Amyloid beta-Peptides; D005456:Fluorescent Dyes; D046911:Macromolecular Substances; D010446:Peptide Fragments; D010718:Phosphatidylserines; D013778:Tetrazolium Salts; D013844:Thiazoles; C075222:amyloid beta-protein (1-42); C022616:thiazolyl blue