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Zn(II)- and Cu(II)- induced non-fibrillar aggregates of amyloid-â (1-42) peptide are transformed to amyloid fibrils, both spontaneously and under the influence of metal chelators
Citation
Tougu, V and Karafin, A and Zovo, K and Chung, RS and Howells, C and West, AK and Palumaa, P, Zn(II)- and Cu(II)- induced non-fibrillar aggregates of amyloid-a (1-42) peptide are transformed to amyloid fibrils, both spontaneously and under the influence of metal chelators, Journal of Neurochemistry, 110, (6) pp. 1784-1795. ISSN 0022-3042 (2009) [Refereed Article]
DOI: doi:10.1111/j.1471-4159.2009.06269.x
Abstract
Aggregation of amyloid-b (Ab) peptides is a central phenomenon
in Alzheimer’s disease. Zn(II) and Cu(II) have profound
effects on Ab aggregation; however, their impact on amyloidogenesis
is unclear. Here we show that Zn(II) and Cu(II)
inhibit Ab42 fibrillization and initiate formation of non-fibrillar
Ab42 aggregates, and that the inhibitory effect of Zn(II)
(IC50 = 1.8 lmol/L) is three times stronger than that of Cu(II).
Medium and high-affinity metal chelators including metallothioneins
prevented metal-induced Ab42 aggregation. Moreover,
their addition to preformed aggregates initiated fast Ab42
fibrillization. Upon prolonged incubation the metal-induced
aggregates also transformed spontaneously into fibrils, that
appear to represent the most stable state of Ab42. H13A and
H14A mutations in Ab42 reduced the inhibitory effect of metal
ions, whereas an H6A mutation had no significant impact. We
suggest that metal binding by H13 and H14 prevents the
formation of a cross-b core structure within region 10–23 of
the amyloid fibril. Cu(II)-Ab42 aggregates were neurotoxic to
neurons in vitro only in the presence of ascorbate, whereas
monomers and Zn(II)-Ab42 aggregates were non-toxic. Disturbed
metal homeostasis in the vicinity of zinc-enriched
neurons might pre-dispose formation of metal-induced Ab
aggregates, subsequent fibrillization of which can lead to
amyloid formation. The molecular background underlying
metal-chelating therapies for Alzheimer’s disease is discussed
in this light.
Item Details
| Item Type: | Refereed Article |
|---|---|
| Keywords: | aggregation, Alzheimer’s disease, amyloid-beta, fibrillization, metal chelating therapy, zinc and copper ions |
| Research Division: | Medical and Health Sciences |
| Research Group: | Neurosciences |
| Research Field: | Neurology and Neuromuscular Diseases |
| Objective Division: | Health |
| Objective Group: | Clinical Health (Organs, Diseases and Abnormal Conditions) |
| Objective Field: | Nervous System and Disorders |
| Author: | Chung, RS (Associate Professor Roger Chung) |
| Author: | Howells, C (Ms Claire Howells) |
| Author: | West, AK (Professor Adrian West) |
| ID Code: | 62155 |
| Year Published: | 2009 |
| Web of Science® Times Cited: | 113 |
| Deposited By: | Menzies Institute for Medical Research |
| Deposited On: | 2010-03-10 |
| Last Modified: | 2010-04-16 |
| Downloads: | 0 |
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