Linked Life Data

21216965

Source:http://linkedlifedata.com/resource/pubmed/id/21216965

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
11
pubmed:dateCreated
2011-3-30
pubmed:abstractText
Abnormally high concentrations of Zn(2+), Cu(2+), and Fe(3+) are present along with amyloid-? (A?) in the senile plaques in Alzheimer disease, where Al(3+) is also detected. A? aggregation is the key pathogenic event in Alzheimer disease, where A? oligomers are the major culprits. The fundamental mechanism of these metal ions on A? 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 A? at the early stage of the aggregation. Furthermore, thioflavin T assay, dot blotting, and transmission electron microscopy are utilized to examine A? aggregation. Our results show that Al(3+) and Zn(2+), but not Cu(2+) and Fe(3+), induce larger hydrophobic exposures of A? conformation, resulting in its significant destabilization at the early stage. The metal ion binding induces A? conformational changes with micromolar binding affinities and millisecond binding kinetics. Cu(2+) and Zn(2+) induce similar assembly of transiently appearing A? 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 A?, where A? destabilization promotes annular protofibril formation. Our study facilitates the understanding of annular A? oligomer formation upon metal ion binding.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Mar
pubmed:issn
1083-351X
pubmed:author
pubmed:issnType
Electronic
pubmed:day
18
pubmed:volume
286
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
9646-56
pubmed:meshHeading
pubmed:year
2011
pubmed:articleTitle
Distinct effects of Zn2+, Cu2+, Fe3+, and Al3+ on amyloid-beta stability, oligomerization, and aggregation: amyloid-beta destabilization promotes annular protofibril formation.
pubmed:affiliation
Genomics Research Center, Academia Sinica, 11574 Taipei, Taiwan.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't