Contrasting, species-dependent modulation of copper-mediated neurotoxicity by the Alzheimer's disease amyloid precursor protein.
The amyloid precursor protein (APP) of Alzheimer's disease (AD) has a copper binding domain (CuBD) located in the N-terminal cysteine-rich region that can strongly bind copper(II) and reduce it to Cu(I) in vitro. The CuBD sequence is similar among the APP family paralogs [amyloid precursor-like proteins (APLP1 and APLP2)] and its orthologs (including Drosophila melanogaster, Xenopus laevis, and Caenorhabditis elegans), suggesting an overall conservation in its function or activity. The APP CuBD is involved in modulating Cu homeostasis and amyloid beta peptide production. In this paper, we demonstrate for the first time that Cu-metallated full-length APP ectodomain induces neuronal cell death in vitro. APP Cu neurotoxicity can be induced directly or potentiated through Cu(I)-mediated oxidation of low-density lipoprotein, a finding that may have important implications for the role of lipoproteins and membrane cholesterol composition in AD. Cu toxicity induced by human APP, Xenopus APP, and APLP2 CuBDs is dependent on conservation of histidine residues at positions corresponding to 147 and 151 of human APP. Intriguingly, APP orthologs with different amino acid residues at these positions had dramatically altered Cu phenotypes. The corresponding C. elegans APL-1 CuBD, which has tyrosine and lysine residues at positions 147 and 151, respectively, strongly protected against Cu-mediated lipid peroxidation and neurotoxicity in vitro. Replacement of histidines 147 and 151 with tyrosine and lysine residues conferred this neuroprotective Cu phenotype to human APP, APLP2, and Xenopus APP CuBD peptides. Moreover, we show that the toxic and protective CuBD phenotypes are associated with differences in Cu binding and reduction. These studies identify a significant evolutionary change in the function of the CuBD in modulating Cu metabolism. Our findings also suggest that targeting of inhibitors to histidine residues at positions 147 and 151 of APP could significantly alter the oxidative potential of APP.
White
Anthony R
AR
Department of Pathology, The University of Melbourne, Victoria 3010, Australia.
Multhaup
Gerd
G
Galatis
Denise
D
McKinstry
William J
WJ
Parker
Michael W
MW
Pipkorn
Rüdiger
R
Beyreuther
Konrad
K
Masters
Colin L
CL
Cappai
Roberto
R
D000544:Alzheimer Disease / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D001665:Binding Sites / Q000235:genetics / Q000502:physiology; D017173:Caenorhabditis elegans; D002478:Cells, Cultured; D017124:Conserved Sequence / Q000235:genetics / Q000502:physiology; D003300:Copper / Q000633:toxicity*; D004330:Drosophila; D005998:Glycine / Q000737:chemistry; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D008077:Lipoproteins, LDL / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D016297:Mutagenesis, Site-Directed; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D009942:Organometallic Compounds / Q000737:chemistry; D010084:Oxidation-Reduction / Q000187:drug effects; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D017434:Protein Structure, Tertiary / Q000235:genetics / Q000502:physiology; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D017386:Sequence Homology, Amino Acid; D013045:Species Specificity; D013329:Structure-Activity Relationship; D023741:Takifugu; D014981:Xenopus
D016564:Amyloid beta-Protein Precursor; D008077:Lipoproteins, LDL; D009942:Organometallic Compounds; D010446:Peptide Fragments; D011994:Recombinant Proteins; C018493:cupric glycinate; D003300:Copper; D005998:Glycine