New Insights on How Metals Disrupt Amyloid β-Aggregation and Their Effects on Amyloid-β Cytotoxicity

Yuji Yoshiike, Kentaro Tanemura, Ohoshi Murayama, Takumi Akagi, Miyuki Murayama, Shinji Sato, Xiaoyan Sun, Nobuo Tanaka, Akihiko Takashima

Research output: Contribution to journalArticle

220 Scopus citations

Abstract

Amyloid-β protein (Aβ) 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 β-aggregation. Another method for detecting Aβ, which does not distinguish the types of aggregates, showed that these metals induce a non-β-sheeted aggregation, as reported previously. Secondary structural analysis and microscopic studies revealed that metals induced Aβ to make non-fibrillar aggregates by disrupting β-sheet formation. These non-fibrillar Aβ aggregates displayed much weaker Congo Red birefringence, and in separate cell culture experiments, were less toxic than self β-aggregates, as demonstrated by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay. The toxicity of soluble Aβ was enhanced in the presence of Cu(II), which suggests the previously hypothesized role of Aβ in generating oxidative stress. Finally, under an acidic condition, similar to that in the inflammation associated with senile plaques, β-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 β-aggregation and its associated cytotoxicity, including its anti-oxidative nature we suggest that Zn(II) has an overall protective effect against β-amyloid toxicity.

Original languageEnglish (US)
Pages (from-to)32293-32299
Number of pages7
JournalJournal of Biological Chemistry
Volume276
Issue number34
DOIs
StatePublished - Aug 24 2001
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Yoshiike, Y., Tanemura, K., Murayama, O., Akagi, T., Murayama, M., Sato, S., Sun, X., Tanaka, N., & Takashima, A. (2001). New Insights on How Metals Disrupt Amyloid β-Aggregation and Their Effects on Amyloid-β Cytotoxicity. Journal of Biological Chemistry, 276(34), 32293-32299. https://doi.org/10.1074/jbc.M010706200