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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
journal contributionposted on 2023-05-17, 01:58 authored by Tougu, V, Karafin, A, Zovo, K, Chung, RS, Howells, C, Adrian WestAdrian West, Palumaa, P
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.
Publication titleJournal of Neurochemistry
Department/SchoolMenzies Institute for Medical Research
PublisherBlackwell Publishing Ltd
Place of publication9600 Garsington Rd, Oxford, England, Oxon, Ox4 2Dg