Journal
JOURNAL OF NEUROCHEMISTRY
Volume 110, Issue 6, Pages 1784-1795Publisher
WILEY
DOI: 10.1111/j.1471-4159.2009.06269.x
Keywords
aggregation; Alzheimer's disease; amyloid-beta; fibrillization; metal chelating therapy; zinc and copper ions
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Funding
- Estonian Science Foundation [6840, 7191]
- World Federation of Scientists scholarship
- Alzheimer's Australia Research
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Aggregation of amyloid-beta (A beta) peptides is a central phenomenon in Alzheimer's disease. Zn(II) and Cu(II) have profound effects on A beta aggregation; however, their impact on amyloidogenesis is unclear. Here we show that Zn(II) and Cu(II) inhibit A beta(42) fibrillization and initiate formation of non-fibrillar A beta(42) aggregates, and that the inhibitory effect of Zn(II) (IC50 = 1.8 mu mol/L) is three times stronger than that of Cu(II). Medium and high-affinity metal chelators including metallothioneins prevented metal-induced A beta(42) aggregation. Moreover, their addition to preformed aggregates initiated fast A beta(42) fibrillization. Upon prolonged incubation the metal-induced aggregates also transformed spontaneously into fibrils, that appear to represent the most stable state of A beta(42). H13A and H14A mutations in A beta(42) 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-beta core structure within region 10-23 of the amyloid fibril. Cu(II)-A beta(42) aggregates were neurotoxic to neurons in vitro only in the presence of ascorbate, whereas monomers and Zn(II)-A beta(42) 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.
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