New insights on how metals disrupt amyloid beta-aggregation and their effects on amyloid-beta cytotoxicity.
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.
Yoshiike
Y
Y
Laboratory for Alzheimer's Disease, Brain Science Institute, RIKEN, Wako, Saitama 351-0198, Japan.
Tanemura
K
K
Murayama
O
O
Akagi
T
T
Murayama
M
M
Sato
S
S
Sun
X
X
Tanaka
N
N
Takashima
A
A
D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D002942:Circular Dichroism; D003300:Copper / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects; D006801:Humans; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D051381:Rats; D015032:Zinc / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D003300:Copper; D015032:Zinc