Toxicity of Alzheimer's disease-associated Aβ peptide is ameliorated in a Drosophila model by tight control of zinc and copper availability

Abstract Amyloid plaques consisting of aggregated Aβ peptide are a hallmark of Alzheimer's disease. Among the different forms of Aβ, the one of 42aa length (Aβ42) is most aggregation-prone and also the most neurotoxic. We find that eye-specific expression of human Aβ42 in Drosophila results in a degeneration of eye structures that progresses with age. Dietary supplements of zinc or copper ions exacerbate eye damage. Positive effects are seen with zinc/copper chelators, or with elevated expression of MTF-1, a transcription factor with a key role in metal homeostasis and detoxification, or with human or fly transgenes encoding metallothioneins, metal scavenger proteins. These results show that a tight control of zinc and copper availability can minimize cellular damage associated with Aβ42 expression.

[1]  W. Schaffner,et al.  The parkin Mutant Phenotype in the Fly Is Largely Rescued by Metal-Responsive Transcription Factor (MTF-1) , 2011, Molecular and Cellular Biology.

[2]  P. Salvaterra,et al.  Brain aging and Aβ1–42 neurotoxicity converge via deterioration in autophagy–lysosomal system: a conditional Drosophila model linking Alzheimer’s neurodegeneration with aging , 2011, Acta Neuropathologica.

[3]  W. Schaffner,et al.  Extended lifespan of Drosophila parkin mutants through sequestration of redox-active metals and enhancement of anti-oxidative pathways , 2010, Neurobiology of Disease.

[4]  Linda Partridge,et al.  Inhibition of GSK-3 Ameliorates Aβ Pathology in an Adult-Onset Drosophila Model of Alzheimer's Disease , 2010, PLoS genetics.

[5]  T. Aigaki,et al.  Insulin‐degrading enzyme antagonizes insulin‐dependent tissue growth and Aβ‐induced neurotoxicity in Drosophila , 2010, FEBS letters.

[6]  W. Schaffner,et al.  Zinc supplement greatly improves the condition of parkin mutant Drosophila , 2010, Biological chemistry.

[7]  M. Vitek,et al.  Apolipoprotein E-Mimetics Inhibit Neurodegeneration and Restore Cognitive Functions in a Transgenic Drosophila Model of Alzheimer's Disease , 2009, PloS one.

[8]  Benjamin R. Rost,et al.  Role of Amyloid-β Glycine 33 in Oligomerization, Toxicity, and Neuronal Plasticity , 2009, The Journal of Neuroscience.

[9]  S. Abdel‐Ghany,et al.  Copper homeostasis. , 2009, The New phytologist.

[10]  Robert Hider,et al.  Fenton chemistry and oxidative stress mediate the toxicity of the β-amyloid peptide in a Drosophila model of Alzheimer’s disease , 2009, The European journal of neuroscience.

[11]  T. Schneider-Axmann,et al.  Effect of copper intake on CSF parameters in patients with mild Alzheimer’s disease: a pilot phase 2 clinical trial , 2008, Journal of Neural Transmission.

[12]  Xudong Huang,et al.  Characterization of copper interactions with alzheimer amyloid beta peptides: identification of an attomolar-affinity copper binding site on amyloid beta1-42. , 2008, Journal of neurochemistry.

[13]  D. Selkoe,et al.  Soluble oligomers of the amyloid β-protein impair synaptic plasticity and behavior , 2008, Behavioural Brain Research.

[14]  T. Schneider-Axmann,et al.  ALZHEIMER’S DISEASE AND RELATED DISORDERS- ORIGINAL ARTICLE Intake , 2022 .

[15]  J. Teissié,et al.  Metal swap between Zn7-metallothionein-3 and amyloid-beta-Cu protects against amyloid-beta toxicity. , 2008, Nature chemical biology.

[16]  E. Levin,et al.  Metallothionein in the central nervous system: Roles in protection, regeneration and cognition. , 2008, Neurotoxicology.

[17]  Oxana V. Baranova,et al.  The lipophilic metal chelators DP‐109 and DP‐460 are neuroprotective in a transgenic mouse model of amyotrophic lateral sclerosis , 2007, Journal of neurochemistry.

[18]  Bernardo L Sabatini,et al.  Natural Oligomers of the Alzheimer Amyloid-β Protein Induce Reversible Synapse Loss by Modulating an NMDA-Type Glutamate Receptor-Dependent Signaling Pathway , 2007, The Journal of Neuroscience.

[19]  D. Egli,et al.  Copper homeostasis in Drosophila by complex interplay of import, storage and behavioral avoidance , 2007, The EMBO journal.

[20]  Astrid Gräslund,et al.  High‐resolution NMR studies of the zinc‐binding site of the Alzheimer's amyloid β‐peptide , 2007 .

[21]  R. Malinow,et al.  AMPAR Removal Underlies Aβ-Induced Synaptic Depression and Dendritic Spine Loss , 2006, Neuron.

[22]  M. Goedert,et al.  A Century of Alzheimer's Disease , 2006, Science.

[23]  D. Egli,et al.  Transcriptome response to heavy metal stress in Drosophila reveals a new zinc transporter that confers resistance to zinc , 2006, Nucleic acids research.

[24]  Walter Schaffner,et al.  Copper homeostasis in eukaryotes: teetering on a tightrope. , 2006, Biochimica et biophysica acta.

[25]  M. Penkowa.  Metallothioneins are multipurpose neuroprotectants during brain pathology , 2006, The FEBS journal.

[26]  Richard M. Page,et al.  Intraneuronal Aβ, non-amyloid aggregates and neurodegeneration in a Drosophila model of Alzheimer’s disease , 2005, Neuroscience.

[27]  R. Jelinek,et al.  Membrane interactions and metal ion effects on bilayer permeation of the lipophilic ion modulator DP-109. , 2005, Biochemistry.

[28]  K. Freeman,et al.  BACE1 Cytoplasmic Domain Interacts with the Copper Chaperone for Superoxide Dismutase-1 and Binds Copper* , 2005, Journal of Biological Chemistry.

[29]  T. Bayer,et al.  Clioquinol Mediates Copper Uptake and Counteracts Copper Efflux Activities of the Amyloid Precursor Protein of Alzheimer's Disease* , 2004, Journal of Biological Chemistry.

[30]  J. Koh,et al.  The lipophilic metal chelator DP-109 reduces amyloid pathology in brains of human β-amyloid precursor protein transgenic mice , 2004, Neurobiology of Aging.

[31]  M. Konsolaki,et al.  A model for studying Alzheimer's Aβ42-induced toxicity in Drosophila melanogaster , 2004, Molecular and Cellular Neuroscience.

[32]  R. Nitsch,et al.  Age-Dependent Neurodegeneration and Alzheimer-Amyloid Plaque Formation in Transgenic Drosophila , 2004, The Journal of Neuroscience.

[33]  A. Bird,et al.  Metal-Responsive Transcription Factors That Regulate Iron, Zinc, and Copper Homeostasis in Eukaryotic Cells , 2004, Eukaryotic Cell.

[34]  T. Bayer,et al.  Dietary Cu stabilizes brain superoxide dismutase 1 activity and reduces amyloid Aβ production in APP23 transgenic mice , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[35]  C. Finch,et al.  Alzheimer's disease-affected brain: Presence of oligomeric Aβ ligands (ADDLs) suggests a molecular basis for reversible memory loss , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[36]  C. Masters,et al.  Structure of the Alzheimer's Disease Amyloid Precursor Protein Copper Binding Domain , 2003, The Journal of Biological Chemistry.

[37]  Carl W. Cotman,et al.  Common Structure of Soluble Amyloid Oligomers Implies Common Mechanism of Pathogenesis , 2003, Science.

[38]  W. Keung,et al.  Anti-amyloid β activity of metallothionein-III is different from its neuronal growth inhibitory activity: structure–activity studies , 2003, Brain Research.

[39]  E. Hafen,et al.  Knockout of ‘metal‐responsive transcription factor’ MTF‐1 in Drosophila by homologous recombination reveals its central role in heavy metal homeostasis , 2003, The EMBO journal.

[40]  C. Masters,et al.  Overexpression of Alzheimer's Disease Amyloid-β Opposes the Age-dependent Elevations of Brain Copper and Iron* , 2002, The Journal of Biological Chemistry.

[41]  Carsten Schmidt,et al.  Evidence for a copper-binding superfamily of the amyloid precursor protein. , 2002, Biochemistry.

[42]  W. Schaffner,et al.  Putting its fingers on stressful situations: the heavy metal‐regulatory transcription factor MTF‐1 , 2001, BioEssays : news and reviews in molecular, cellular and developmental biology.

[43]  G. Andrews.  Cellular zinc sensors: MTF-1 regulation of gene expression , 2001, Biometals.

[44]  P. Ince,et al.  Mitochondrial enzyme-deficient hippocampal neurons and choroidal cells in AD , 2001, Neurology.

[45]  C. Masters,et al.  Treatment with a Copper-Zinc Chelator Markedly and Rapidly Inhibits β-Amyloid Accumulation in Alzheimer's Disease Transgenic Mice , 2001, Neuron.

[46]  D. Selkoe.  Alzheimer's disease: genes, proteins, and therapy. , 2001, Physiological reviews.

[47]  H. Möller,et al.  A selective defect of cytochrome c oxidase is present in brain of Alzheimer disease patients , 2000, Neurobiology of Aging.

[48]  C. Masters,et al.  Aqueous Dissolution of Alzheimer’s Disease Aβ Amyloid Deposits by Biometal Depletion* , 1999, The Journal of Biological Chemistry.

[49]  Xudong Huang,et al.  The A beta peptide of Alzheimer's disease directly produces hydrogen peroxide through metal ion reduction. , 1999, Biochemistry.

[50]  J. D. Robertson,et al.  Copper, iron and zinc in Alzheimer's disease senile plaques , 1998, Journal of the Neurological Sciences.

[51]  Xudong Huang,et al.  Dramatic Aggregation of Alzheimer Aβ by Cu(II) Is Induced by Conditions Representing Physiological Acidosis* , 1998, The Journal of Biological Chemistry.

[52]  W. Markesbery,et al.  Four-Hydroxynonenal, a Product of Lipid Peroxidation, is Increased in the Brain in Alzheimer’s Disease , 1998, Neurobiology of Aging.

[53]  C. Masters,et al.  Rapid induction of Alzheimer A beta amyloid formation by zinc. , 1994, Science.

[54]  Y. Uchida,et al.  Growth-inhibitory factor, metallothionein-like protein, and neurodegenerative diseases. , 1994, Biological signals.

[55]  R. Palmiter,et al.  Enhanced neurotrophic activity in Alzheimer's disease cortex is not associated with down-regulation of metallothionein-III (GIF) , 1994, Brain Research.

[56]  D. Brems,et al.  Secondary structure of amyloid beta peptide correlates with neurotoxic activity in vitro. , 1994, Molecular pharmacology.

[57]  W. Schaffner,et al.  Cloned transcription factor MTF‐1 activates the mouse metallothionein I promoter. , 1993, The EMBO journal.

[58]  K. Titani,et al.  The growth inhibitory factor that is deficient in the Alzheimer's disease brain is a 68 amino acid metallothionein-like protein , 1991, Neuron.

[59]  K. Grzeschik,et al.  The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor , 1987, Nature.

[60]  W. Schaffner,et al.  Parkin mutant in the fly is largely rescued by metal-responsive 1 transcription factor ( MTF-1 ) 2 3 , 2011 .

[61]  J. Danielsson,et al.  High-resolution NMR studies of the zinc-binding site of the Alzheimer's amyloid beta-peptide. , 2007, The FEBS journal.

[62]  Damian C Crowther,et al.  A Drosophila model of Alzheimer's disease. , 2006, Methods in enzymology.

[63]  D. Gubb,et al.  Intraneuronal Abeta, non-amyloid aggregates and neurodegeneration in a Drosophila model of Alzheimer's disease. , 2005, Neuroscience.