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.
Subject(s)
Amyloid beta-Peptides/metabolism , Endopeptidases/metabolism , Zinc/metabolism , Zinc/pharmacology , Amyloid Precursor Protein Secretases , Amyloid beta-Peptides/chemistry , Amyloid beta-Peptides/isolation & purification , Aspartic Acid Endopeptidases , Binding Sites , Chromatography, Gel , Copper/pharmacology , Edetic Acid/pharmacology , Humans , Hydrogen-Ion Concentration , Kaolin , Kinetics , Metals/pharmacologyABSTRACT
Familial Alzheimer's disease (FAD) is a genetically heterogeneous disorder that includes a rare early-onset form linked to mutations in the amyloid b protein precursor (APP) gene. Clues to the function of APP derive from the recent finding that it is a member of a highly conserved protein family that includes the mammalian amyloid precursor-like protein (APLP1) gene which maps to the same general region of human chromosome 19 linked to late-onset FAD. Here we report the isolation of the human APLP2 gene. We show that APLP2 is a close relative of APP and exhibits a very similar pattern of expression in the brain and throughout the body. Like APP, APLP2 contains a cytoplasmic domain predicted to couple with the GTP-binding protein G(o) indicating that it may be an additional cell surface activator of this G protein.
