New insights on how metals disrupt amyloid beta-aggregation and their effects on amyloid-beta cytotoxicity

• Published in: The Journal of biological chemistry Vol. 276; no. 34; pp. 32293 - 32299
• Main Authors: Yoshiike, Y, Tanemura, K, Murayama, O, Akagi, T, Murayama, M, Sato, S, Sun, X, Tanaka, N, Takashima, A
• Format: Journal Article
• Language: English
• Published: United States 24.08.2001
• Subjects: Amyloid beta-Peptides - metabolism; Amyloid beta-Peptides - physiology; Animals; Cell Death - drug effects; Cell Line; Cell Survival - drug effects; Cell Survival - physiology; Cells, Cultured; Circular Dichroism; Copper - pharmacology; Hippocampus - cytology; Hippocampus - drug effects; Humans; Neurons - cytology; Neurons - drug effects; Rats; Zinc - pharmacology
• ISSN: 0021-9258
• DOI: 10.1074/jbc.M010706200

Amyloid-beta protein (A beta) aggregates in the brain to form senile plaques. By using thioflavin T, a dye that specifically binds to fibrillar structures, we found that metals such as Zn(II) and Cu(II) normally inhibit amyloid beta-aggregation. Another method for detecting A beta, which does not distinguish the types of aggregates, showed that these metals induce a non-beta-sheeted aggregation, as reported previously. Secondary structural analysis and microscopic studies revealed that metals induced A beta to make non-fibrillar aggregates by disrupting beta-sheet formation. These non-fibrillar A beta aggregates displayed much weaker Congo Red birefringence, and in separate cell culture experiments, were less toxic than self beta-aggregates, as demonstrated by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay. The toxicity of soluble A beta was enhanced in the presence of Cu(II), which suggests the previously hypothesized role of A beta in generating oxidative stress. Finally, under an acidic condition, similar to that in the inflammation associated with senile plaques, beta-aggregation was robustly facilitated at one specific concentration of Zn(II) in the presence of heparin. However, because a higher concentration of Zn(II) virtually abolished this abnormal phenomenon, and at normal pH any concentrations strongly inhibit beta-aggregation and its associated cytotoxicity, including its anti-oxidative nature we suggest that Zn(II) has an overall protective effect against beta-amyloid toxicity.