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Please use this identifier to cite or link to this item: http://hdl.handle.net/1959.14/225078
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- Title
- Zn(II)- and Cu(II)-induced non-fibrillar aggregates of amyloid-β (1-42) peptide are transformed to amyloid fibrils, both spontaneously and under the influence of metal chelators
- Related
- Journal of neurochemistry, Vol. 110, Issue 6, (2009), p.1784-1795
- DOI
- 10.1111/j.1471-4159.2009.06269.x
- Publisher
- Wiley-Blackwell Publishing
- Date
- 2009
- Author/Creator
- Tõugu, Vello
- Author/Creator
- Karafin, Ann
- Author/Creator
- Zovo, Kairit
- Author/Creator
- Chung, Roger S
- Author/Creator
- Howells, Claire
- Author/Creator
- West, Adrian K
- Author/Creator
- Palumaa, Peep
- Description
- Aggregation of amyloid-β (Aβ) peptides is a central phenomenon in Alzheimer's disease. Zn(II) and Cu(II) have profound effects on Aβ aggregation; however, their impact on amyloidogenesis is unclear. Here we show that Zn(II) and Cu(II) inhibit Aβ₄₂ fibrillization and initiate formation of non-fibrillar Aβ₄₂ aggregates, and that the inhibitory effect of Zn(II) (IC₅₀ = 1.8 μmol/L) is three times stronger than that of Cu(II). Medium and high-affinity metal chelators including metallothioneins prevented metal-induced Aβ₄₂ aggregation. Moreover, their addition to preformed aggregates initiated fast Aβ₄₂ fibrillization. Upon prolonged incubation the metal-induced aggregates also transformed spontaneously into fibrils, that appear to represent the most stable state of Aβ₄₂. H13A and H14A mutations in Aβ₄₂ 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-β core structure within region 10-23 of the amyloid fibril. Cu(II)-Aβ₄₂ aggregates were neurotoxic to neurons in vitro only in the presence of ascorbate, whereas monomers and Zn(II)-Aβ₄₂ aggregates were non-toxic. Disturbed metal homeostasis in the vicinity of zinc-enriched neurons might pre-dispose formation of metal-induced Aβ 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.
- Description
- 12 page(s)
- Subject Keyword
- 110900 Neurosciences
- Subject Keyword
- Aggregation
- Subject Keyword
- Alzheimer's disease
- Subject Keyword
- Amyloid-β
- Subject Keyword
- Fibrillization
- Subject Keyword
- Metal chelating therapy
- Subject Keyword
- Zinc and copper ions
- Resource Type
- journal article
- Organisation
- Macquarie University. Australian School of Advanced Medicine
- Identifier
- http://hdl.handle.net/1959.14/225078
- Identifier
- mq:26757
- Identifier
- ISSN:0022-3042
- Identifier
- mq-rm-2011014406
- Identifier
- mq_res-ext-2-s2.0-69949167074
- Language
- eng
- Reviewed
Macquarie University ResearchOnline
