title: Zinc and Copper Differentially Modulate Amyloid Precursor Protein Processing by γ-Secretase and Amyloid-β Peptide Production.
abstract: Recent evidence suggests involvement of biometal homeostasis in the pathological mechanisms in Alzheimer's disease (AD). For example, increased intracellular copper or zinc has been linked to a reduction in secreted levels of the AD-causing amyloid-β peptide (Aβ). However, little is known about whether these biometals modulate the generation of Aβ. In the present study we demonstrate in both cell-free and cell-based assays that zinc and copper regulate Aβ production by distinct molecular mechanisms affecting the processing by γ-secretase of its Aβ precursor protein substrate APP-C99. We found that Zn2+induces APP-C99 dimerization, which prevents its cleavage by γ-secretase and Aβ production, with an IC50value of 15 μm Importantly, at this concentration, Zn2+also drastically raised the production of the aggregation-prone Aβ43 found in the senile plaques of AD brains and elevated the Aβ43:Aβ40 ratio, a promising biomarker for neurotoxicity and AD. We further demonstrate that the APP-C99 histidine residues His-6, His-13, and His-14 control the Zn2+-dependent APP-C99 dimerization and inhibition of Aβ production, whereas the increased Aβ43:Aβ40 ratio is substrate dimerization-independent and involves the known Zn2+binding lysine Lys-28 residue that orientates the APP-C99 transmembrane domain within the lipid bilayer. Unlike zinc, copper inhibited Aβ production by directly targeting the subunits presenilin and nicastrin in the γ-secretase complex. Altogether, our data demonstrate that zinc and copper differentially modulate Aβ production. They further suggest that dimerization of APP-C99 or the specific targeting of individual residues regulating the production of the long, toxic Aβ species, may offer two therapeutic strategies for preventing AD.
authors.affiliation: From the Foundation Eclosion, CH-1228 Plan-Les-Ouates, and Campus Biotech Innovation Park, CH-1202 Geneva, Switzerland.|the Brain Mind Institute and School of Life Sciences, Swiss Federal Institute of Technology (EPFL), CH-1015 Lausanne, Switzerland.|the Department of Biology, University of Fribourg, CH-1700 Fribourg, Switzerland, and.
authors.forename: Hermeto
authors.initials: H
authors.lastname: Gerber
authors.affiliation: the Brain Mind Institute and School of Life Sciences, Swiss Federal Institute of Technology (EPFL), CH-1015 Lausanne, Switzerland.|the Key Laboratory of Systems Biomedicine, Ministry of Education, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, 200240 Shanghai, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Wu
authors.affiliation: the Brain Mind Institute and School of Life Sciences, Swiss Federal Institute of Technology (EPFL), CH-1015 Lausanne, Switzerland.
authors.forename: Mitko
authors.initials: M
authors.lastname: Dimitrov
authors.affiliation: the Brain Mind Institute and School of Life Sciences, Swiss Federal Institute of Technology (EPFL), CH-1015 Lausanne, Switzerland.
authors.forename: Guillermo M
authors.initials: GM
authors.lastname: Garcia Osuna
authors.affiliation: From the Foundation Eclosion, CH-1228 Plan-Les-Ouates, and Campus Biotech Innovation Park, CH-1202 Geneva, Switzerland, fraeringpatrick@hotmail.com.|the Brain Mind Institute and School of Life Sciences, Swiss Federal Institute of Technology (EPFL), CH-1015 Lausanne, Switzerland.
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Fraering
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D002474:Cell-Free System; D003300:Copper / Q000737:chemistry*; D057809:HEK293 Cells; D006639:Histidine / Q000737:chemistry; D006801:Humans; D020128:Inhibitory Concentration 50; D008051:Lipid Bilayers / Q000737:chemistry; D008239:Lysine / Q000737:chemistry; D008562:Membrane Glycoproteins / Q000378:metabolism; D009154:Mutation; D010446:Peptide Fragments / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D053763:Presenilins / Q000378:metabolism; D000072417:Protein Domains; D055503:Protein Multimerization; D011994:Recombinant Proteins / Q000378:metabolism; D015032:Zinc / Q000737:chemistry*
chemical_list: C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D008051:Lipid Bilayers; D008562:Membrane Glycoproteins; D010446:Peptide Fragments; D053763:Presenilins; D011994:Recombinant Proteins; C413604:nicastrin protein; D006639:Histidine; D003300:Copper; D053829:Amyloid Precursor Protein Secretases; D015032:Zinc; D008239:Lysine
keywords: Alzheimer disease; amyloid precursor protein (APP); amyloid-β (AB); biometals; copper; intramembrane proteolysis; neurodegeneration; zinc