Modulation of A beta adhesiveness and secretase site cleavage by zinc.
Abnormalities of zinc homeostasis occur in Alzheimer's disease (AD), a dementia characterized by the aggregation of A beta in the brain, and in Down syndrome, a condition characterized by premature AD. We studied the binding of Zn2+ to a synthetic peptide representing residues 1-40 (A beta 1-40), as well as other domains of A beta. Two classes of Zn2+ binding were identified by 65Zn2+ labeling: highly specific pH-dependent high affinity (K(a) = 107 nM) binding, and lower affinity (K(a) = 5.2 microM) binding. Gel filtration chromatography identified monomeric, dimeric, and polymeric A beta species. Zinc induced a marked loss of A beta solubility upon chromatographic analysis. This was attributed to precipitation onto the column glass, which contains aluminosilicate, and was confirmed by the observation of zinc-accelerated precipitation of A beta by kaolin, a hydrated aluminum silicate suspension. Zinc binding also increased A beta resistance to tryptic cleavage at the secretase site, indicating that a small (<3 microM) increase in brain Zn2+ concentration could significantly alter A beta metabolism. We propose that elevated brain interstitial zinc levels may increase A beta adhesiveness and interfere with A beta catabolism. Consequently, abnormalities of regional zinc concentrations in the brains of patients with AD or Down syndrome may contribute to A beta amyloidosis in these disorders.
Bush
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Laboratory of Genetics and Aging, Massachusetts General Hospital, Harvard Medical School, Boston 02129.
Pettingell
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Paradis
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Tanzi
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D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D016282:Aspartic Acid Endopeptidases; D001665:Binding Sites; D002850:Chromatography, Gel; D003300:Copper / Q000494:pharmacology; D004492:Edetic Acid / Q000494:pharmacology; D010450:Endopeptidases / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007616:Kaolin; D007700:Kinetics; D008670:Metals / Q000494:pharmacology; D015032:Zinc / Q000378:metabolism* / Q000494:pharmacology*
D016229:Amyloid beta-Peptides; D008670:Metals; D007616:Kaolin; D003300:Copper; D004492:Edetic Acid; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D015032:Zinc