Zinc and copper ions induce the aggregation of Αβ peptides

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Alzheimer's disease (AD) is a neurodegenerative disease characterized by deposits of extracellular amyloid plaques and intracellular neurofibrillary tangles in the brain. The principal components of the plaques are fibrils formed of 40–42 residues long amyloid β-peptides (Αβ) derived from cleavage of amyloid precursor protein (APP) by β- and γ-secretases. Αβ aggregation is an established pathogenic mechanism of AD and therefore factors influencing the Αβ aggregation are of high interest. Aggregation of Αβ peptides is primarily affected by a variety of genetic and dietary factors leading to increased concentrations of Αβ peptides or to the excessive formation of Αβ peptides with increased tendency for aggregation i and copper ions may induce the aggregation of Αβ peptides and these ligands may act as seeding factors in the formation of amyloid plaques. Cu2+ and Zn2+ form complexes with Abeta peptides in vitro; however, the published metal-binding affinities of Abeta vary in an enormously large range. Authors studied the interactions of Cu2+ and Zn2+ with monomeric Abeta(40) under different conditions using intrinsic Abeta fluorescence and metal-selective fluorescent dyes. We showed that Cu(2+) forms a stable and soluble 1 : 1 complex with Abeta(40), however, buffer compounds act as competitive copper-binding ligands and affect the apparent K(D). Buffer-independent conditional K(D) for Cu(II)-Abeta(40) complex at pH 7.4 is equal to 0.035 micromol/L. Interaction of Abeta(40) with Zn2+ is more complicated as partial aggregation of the peptide occurs during zinc titration experiment and in the same time period (within 30 min) the initial Zn-Abeta(40) complex (K(D) = 60 micromol/L) undergoes a transition to a more tight complex with K(D) approximately 2 micromol/L. Competition of Abeta(40) with ion-selective fluorescent dyes Phen Green and Zincon showed that the K(D) values determined from intrinsic fluorescence of Abeta correspond to the binding of the first Cu2+ and Zn2+ ions to the peptide with the highest affinity. Interaction of both Zn2+ and Cu2+ ions with Abeta peptides may occur in brain areas affected by Alzheimer's disease and Zn2+-induced transition in the peptide structure might contribute to amyloid plaque formation. http://www3.interscience.wiley.com/cgi-bin

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