Acidic pH promotes the formation of toxic fibrils from β-amyloid peptide

Beta-amyloid (Aβ) 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 Aβs, which seems to be a prerequisite for their neuropathogenicity, elucidating the aggregation behavior of Aβs 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 Aβ_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 Aβ_1-42 peptides formed large and complex fibrils much more efficiently at acidic rather than neutral pH. Furthermore, only the pH 5.8 Aβ 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 Aβs present in the acidic organelles may form neurotoxic fibrils more easily than those in the neutral cellular compartments.