Modulation of A beta adhesiveness and secretase site cleavage by zinc

J Biol Chem. 1994 Apr 22;269(16):12152-8.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amyloid Precursor Protein Secretases
  • Amyloid beta-Peptides / chemistry
  • Amyloid beta-Peptides / isolation & purification
  • Amyloid beta-Peptides / metabolism*
  • Aspartic Acid Endopeptidases
  • Binding Sites
  • Chromatography, Gel
  • Copper / pharmacology
  • Edetic Acid / pharmacology
  • Endopeptidases / metabolism*
  • Humans
  • Hydrogen-Ion Concentration
  • Kaolin
  • Kinetics
  • Metals / pharmacology
  • Zinc / metabolism*
  • Zinc / pharmacology*

Substances

  • Amyloid beta-Peptides
  • Metals
  • Kaolin
  • Copper
  • Edetic Acid
  • Amyloid Precursor Protein Secretases
  • Endopeptidases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human
  • Zinc