Distinct effects of Zn2+, Cu2+, Fe3+, and Al3+ on amyloid-beta stability, oligomerization, and aggregation: amyloid-beta destabilization promotes annular protofibril formation.
J Biol Chem
; 286(11): 9646-56, 2011 Mar 18.
Article
en En
| MEDLINE
| ID: mdl-21216965
ABSTRACT
Abnormally high concentrations of Zn(2+), Cu(2+), and Fe(3+) are present along with amyloid-ß (Aß) in the senile plaques in Alzheimer disease, where Al(3+) is also detected. Aß aggregation is the key pathogenic event in Alzheimer disease, where Aß oligomers are the major culprits. The fundamental mechanism of these metal ions on Aß remains elusive. Here, we employ 4,4'-Bis(1-anilinonaphthalene 8-sulfonate) and tyrosine fluorescence, CD, stopped flow fluorescence, guanidine hydrochloride denaturation, and photo-induced cross-linking to elucidate the effect of Zn(2+), Cu(2+), Fe(3+), and Al(3+) on Aß at the early stage of the aggregation. Furthermore, thioflavin T assay, dot blotting, and transmission electron microscopy are utilized to examine Aß aggregation. Our results show that Al(3+) and Zn(2+), but not Cu(2+) and Fe(3+), induce larger hydrophobic exposures of Aß conformation, resulting in its significant destabilization at the early stage. The metal ion binding induces Aß conformational changes with micromolar binding affinities and millisecond binding kinetics. Cu(2+) and Zn(2+) induce similar assembly of transiently appearing Aß oligomers at the early state. During the aggregation, we found that Zn(2+) exclusively promotes the annular protofibril formation without undergoing a nucleation process, whereas Cu(2+) and Fe(3+) inhibit fibril formation by prolonging the nucleation phases. Al(3+) also inhibits fibril formation; however, the annular oligomers co-exist in the aggregation pathway. In conclusion, Zn(2+), Cu(2+), Fe(3+), and Al(3+) adopt distinct folding and aggregation mechanisms to affect Aß, where Aß destabilization promotes annular protofibril formation. Our study facilitates the understanding of annular Aß oligomer formation upon metal ion binding.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Zinc
/
Precursor de Proteína beta-Amiloide
/
Cobre
/
Aluminio
/
Amiloide
/
Hierro
Límite:
Humans
Idioma:
En
Revista:
J Biol Chem
Año:
2011
Tipo del documento:
Article
País de afiliación:
Taiwán