Abundant expression of zinc transporters in the amyloid plaques of Alzheimer's disease brain

The pathological key features of Alzheimer's disease (AD) are beta-amyloid peptide (Abeta)-containing senile plaques (SP) and neurofibrillary tangles. Previous studies have suggested that an extracellular elevation of the zinc concentration can initiate the deposition of Abeta and lead to the formation of SP. In the present study, we present data showing a correlation between zinc ions, zinc transporters (ZNTs) and AD, using immersion autometallography (AMG) and double immunofluorescence for the ZNTs and Abeta. We found that all the ZNTs tested (ZNT1, 3, 4, 5, 6, 7) were extensively present in the Abeta-positive plaques in the cortex of human AD brains, and the density of autometallographic silver enhanced zinc-sulphur nanoparticles were much higher in the plaques than in the surrounding zinc enriched (ZEN) terminals. Moreover, we found an abundant expression of ZNT3 and autometallographic grains in the amyloid angiopathic vessels. The subcellular localization of ZNTs and zinc ions were not detected, due to the limited tissue preservation in the present study. In conclusion, our data provided significant morphological evidence of zinc ions and ZNTs being actively involved in the pathological processes that lead to plaque formation.

[1]  M. Stoltenberg,et al.  Amyloid plaques arise from zinc-enriched cortical layers in APP/PS1 transgenic mice and are paradoxically enlarged with dietary zinc deficiency , 2007, Neuroscience.

[2]  R. Palmiter,et al.  Neuronal Zinc Exchange with the Blood Vessel Wall Promotes Cerebral Amyloid Angiopathy in an Animal Model of Alzheimer's Disease , 2004, The Journal of Neuroscience.

[3]  Liping Huang,et al.  Zinc transporter 7 is located in the cis-Golgi apparatus of mouse choroid epithelial cells , 2006, Neuroreport.

[4]  I. Sekler,et al.  Postnatal regulation of ZnT-1 expression in the mouse brain. , 2002, Brain research. Developmental brain research.

[5]  R. Cousins,et al.  Zinc transporters 1, 2 and 4 are differentially expressed and localized in rats during pregnancy and lactation. , 2003, The Journal of nutrition.

[6]  S. Ledoux,et al.  The Amyloid β Protein Induces Oxidative Damage of Mitochondrial DNA , 1997 .

[7]  K. Blennow,et al.  Zinc and copper modulate Alzheimer Aβ levels in human cerebrospinal fluid , 2009, Neurobiology of Aging.

[8]  A. Dahlström,et al.  Zinc transporter 3 and zinc ions in the rodent superior cervical ganglion neurons , 2003, Neuroscience.

[9]  R. Palmiter,et al.  ZnT‐2, a mammalian protein that confers resistance to zinc by facilitating vesicular sequestration. , 1996, The EMBO journal.

[10]  R. Palmiter,et al.  Mouse zinc transporter 1 gene provides an essential function during early embryonic development , 2004, Genesis.

[11]  W. H. Betts,et al.  Correlation of apoptosis with change in intracellular labile Zn(II) using zinquin [(2-methyl-8-p-toluenesulphonamido-6-quinolyloxy)acetic acid], a new specific fluorescent probe for Zn(II). , 1993, The Biochemical journal.

[12]  A. Favier,et al.  In silico identification and expression of SLC30 family genes: An expressed sequence tag data mining strategy for the characterization of zinc transporters' tissue expression , 2004, BMC Genomics.

[13]  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.

[14]  Ling Xie,et al.  Alzheimer's β-Amyloid Peptides Compete for Insulin Binding to the Insulin Receptor , 2002, The Journal of Neuroscience.

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

[16]  D. Selkoe,et al.  Functional γ-secretase complex assembly in Golgi/trans-Golgi network: interactions among presenilin, nicastrin, Aph1, Pen-2, and γ-secretase substrates , 2003, Neurobiology of Disease.

[17]  C. Carter,et al.  Convergence of genes implicated in Alzheimer's disease on the cerebral cholesterol shuttle: APP, cholesterol, lipoproteins, and atherosclerosis , 2007, Neurochemistry International.

[18]  G. Danscher,et al.  Inhibitory zinc-enriched terminals in the mouse cerebellum: double-immunohistochemistry for zinc transporter 3 and glutamate decarboxylase , 2002, Neuroscience Letters.

[19]  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.

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

[21]  R. Palmiter,et al.  Elimination of zinc from synaptic vesicles in the intact mouse brain by disruption of the ZnT3 gene. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[22]  Xiongwei Zhu,et al.  Involvement of Oxidative Stress in Alzheimer Disease , 2006, Journal of neuropathology and experimental neurology.

[23]  R. Tanzi,et al.  Modulation of A beta adhesiveness and secretase site cleavage by zinc. , 1994, The Journal of biological chemistry.

[24]  I. Paulsen,et al.  A Novel Family of Ubiquitous Heavy Metal Ion Transport Proteins , 1997, The Journal of Membrane Biology.

[25]  D. Westaway,et al.  Interactions between β-amyloid and central cholinergic neurons: implications for Alzheimer’s disease , 2004 .

[26]  N. Marks,et al.  Neurosecretases provide strategies to treat sporadic and familial Alzheimer disorders , 2008, Neurochemistry International.

[27]  T. Govezensky,et al.  Amyloid-β peptide binds to microtubule-associated protein 1B (MAP1B) , 2008, Neurochemistry International.

[28]  E. D. Harris.  Cellular transporters for zinc. , 2002, Nutrition reviews.

[29]  Sang Won Suh,et al.  Histochemically-reactive zinc in amyloid plaques, angiopathy, and degenerating neurons of Alzheimer's diseased brains , 2000, Brain Research.

[30]  A. Favier,et al.  Identification and cloning of a beta-cell-specific zinc transporter, ZnT-8, localized into insulin secretory granules. , 2004, Diabetes.

[31]  G. Andrews,et al.  The Transcription Factor MTF-1 Mediates Metal Regulation of the Mouse ZnT1 Gene* , 2000, The Journal of Biological Chemistry.

[32]  R. Ravid,et al.  Increased amount of zinc in the hippocampus and amygdala of Alzheimer's diseased brains A proton-induced X-ray emission spectroscopic analysis of cryostat sections from autopsy material , 1997, Journal of Neuroscience Methods.

[33]  Jae-Young Koh,et al.  Contribution by synaptic zinc to the gender-disparate plaque formation in human Swedish mutant APP transgenic mice , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[34]  F. Shie,et al.  Early intraneuronal Aβ deposition in the hippocampus of APP transgenic mice , 2003 .

[35]  S. Clemens,et al.  Characterization of the ZAT1p zinc transporter from Arabidopsis thaliana in microbial model organisms and reconstituted proteoliposomes , 2002, Planta.

[36]  W. Markesbery,et al.  Elevated Zinc Transporter-6 in Mild Cognitive Impairment, Alzheimer Disease, and Pick Disease , 2006, Journal of neuropathology and experimental neurology.

[37]  Liping Huang,et al.  Functional Characterization of a Novel Mammalian Zinc Transporter, ZnT6* , 2002, The Journal of Biological Chemistry.

[38]  R. Palmiter,et al.  Cloning and functional characterization of a mammalian zinc transporter that confers resistance to zinc. , 1995, The EMBO journal.

[39]  Brian J Bacskai,et al.  Plaque-Derived Oxidative Stress Mediates Distorted Neurite Trajectories in the Alzheimer Mouse Model , 2006, Journal of neuropathology and experimental neurology.

[40]  Xi Chen,et al.  Materials and Methods Som Text Figs. S1 and S2 Table S1 References Abad Directly Links A␤ to Mitochondrial Toxicity in Alzheimer's Disease , 2022 .

[41]  R. Cousins,et al.  Regulation of the zinc transporter ZnT-1 by dietary zinc. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[42]  M. Stoltenberg,et al.  Silver enhancement of quantum dots resulting from (1) metabolism of toxic metals in animals and humans, (2) in vivo, in vitro and immersion created zinc-sulphur/zinc-selenium nanocrystals, (3) metal ions liberated from metal implants and particles. , 2006, Progress in histochemistry and cytochemistry.

[43]  Liping Huang,et al.  Immunohistochemical Analysis of ZnT1, 4, 5, 6, and 7 in the Mouse Gastrointestinal Tract , 2007, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[44]  J. Troncoso,et al.  Immersion autometallographic tracing of zinc ions in Alzheimer beta-amyloid plaques , 2005, Histochemistry and Cell Biology.

[45]  D. Eide,et al.  Eukaryotic zinc transporters and their regulation , 2001, Biometals.

[46]  R. Cousins,et al.  Integrative aspects of zinc transporters. , 2000, The Journal of nutrition.

[47]  G. Danscher.  Exogenous selenium in the brain , 1982, Histochemistry.

[48]  W. D. Ehmann,et al.  Copper, iron, and zinc imbalances in severely degenerated brain regions in Alzheimer's disease: possible relation to oxidative stress , 1996, Journal of the Neurological Sciences.

[49]  M. Tohyama,et al.  Expression of Zinc Transporter Gene, ZnT-1, Is Induced after Transient Forebrain Ischemia in the Gerbil , 1997, The Journal of Neuroscience.

[50]  R. Palmiter,et al.  ZnT-3, a putative transporter of zinc into synaptic vesicles. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[51]  E. Kasarskis,et al.  A quinoline fluorescence method for visualizing and assaying the histochemically reactive zinc (bouton zinc) in the brain , 1987, Journal of Neuroscience Methods.

[52]  R. Palmiter,et al.  Ultrastructural localization of zinc transporter-3 (ZnT-3) to synaptic vesicle membranes within mossy fiber boutons in the hippocampus of mouse and monkey. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[53]  G. Danscher,et al.  Histochemical demonstration of heavy metals , 1981, Histochemistry.

[54]  S. Davis,et al.  Metallothionein knockout and transgenic mice exhibit altered intestinal processing of zinc with uniform zinc-dependent zinc transporter-1 expression. , 1998, The Journal of nutrition.

[55]  R. Frozza,et al.  β-Amyloid peptide toxicity in organotypic hippocampal slice culture involves Akt/PKB, GSK-3β, and PTEN , 2007, Neurochemistry International.

[56]  P. Greengard,et al.  Intraneuronal Alzheimer abeta42 accumulates in multivesicular bodies and is associated with synaptic pathology. , 2002, The American journal of pathology.

[57]  A. Dahlström,et al.  Dynamic zinc pools in mouse choroid plexus , 2004, Neuroreport.

[58]  Liping Huang,et al.  A novel gene involved in zinc transport is deficient in the lethal milk mouse , 1997, Nature Genetics.

[59]  N. Krebs,et al.  Overview of zinc absorption and excretion in the human gastrointestinal tract. , 2000, The Journal of nutrition.

[60]  S. Kelleher,et al.  Zinc transporters in the rat mammary gland respond to marginal zinc and vitamin A intakes during lactation. , 2002, The Journal of nutrition.

[61]  Oliver Wirths,et al.  Intraneuronal Aβ accumulation precedes plaque formation in β-amyloid precursor protein and presenilin-1 double-transgenic mice , 2001, Neuroscience Letters.

[62]  G. Perozzi,et al.  Cloning, expression, and vesicular localization of zinc transporter Dri 27/ZnT4 in intestinal tissue and cells. , 1999, American journal of physiology. Gastrointestinal and liver physiology.

[63]  A. Bush.  Metal complexing agents as therapies for Alzheimer’s disease , 2002, Neurobiology of Aging.

[64]  A. Michalczyk,et al.  Constitutive expression of hZnT4 zinc transporter in human breast epithelial cells. , 2002, The Biochemical journal.

[65]  R. Tanzi,et al.  Role of free radicals and metal ions in the pathogenesis of Alzheimer's disease. , 1999, Metal ions in biological systems.

[66]  V. Chow,et al.  The novel human HUEL (C4orf1) gene maps to chromosome 4p12-p13 and encodes a nuclear protein containing the nuclear receptor interaction motif. , 1999, Genomics.

[67]  George Perry,et al.  Metal binding and oxidation of amyloid-beta within isolated senile plaque cores: Raman microscopic evidence. , 2003, Biochemistry.

[68]  G. Danscher,et al.  Effect of diethyldithiocarbamate (DEDTC) on sulphide silver stained boutons reversible blocking of Timm's sulphide silver stain for “heavy” metals in DEDTC treated rats (Light Microscopy) , 1973, Experimental Brain Research.

[69]  I. Sekler,et al.  Distribution of the zinc transporter ZnT‐1 in comparison with chelatable zinc in the mouse brain , 2002, The Journal of comparative neurology.

[70]  M. Stoltenberg,et al.  Immersion Autometallography: Histochemical In Situ Capturing of Zinc Ions in Catalytic Zinc-Sulfur Nanocrystals , 2004, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[71]  W. Markesbery,et al.  Alterations in zinc transporter protein-1 (ZnT-1) in the brain of subjects with mild cognitive impairment, early, and late-stage alzheimer’s disease , 2009, Neurotoxicity Research.

[72]  A. Bush,et al.  Metals and neuroscience. , 2000, Current opinion in chemical biology.

[73]  M. Nagao,et al.  Overview of mammalian zinc transporters , 2003, Cellular and Molecular Life Sciences CMLS.

[74]  W. D. Ehmann,et al.  Elemental imbalances in the olfactory pathway in Alzheimer's disease , 1995, Journal of the Neurological Sciences.

[75]  J. L. Smith,et al.  Altered expression of zinc transporters-4 and -6 in mild cognitive impairment, early and late Alzheimer’s disease brain , 2006, Neuroscience.

[76]  P. Faller,et al.  Zinc binding to amyloid-beta: isothermal titration calorimetry and Zn competition experiments with Zn sensors. , 2007, Biochemistry.

[77]  Antonio Lanzirotti,et al.  Synchrotron-based infrared and X-ray imaging shows focalized accumulation of Cu and Zn co-localized with beta-amyloid deposits in Alzheimer's disease. , 2006, Journal of structural biology.

[78]  A. Dahlström,et al.  Abundant expression of zinc transporters in Bergman glia of mouse cerebellum , 2005, Brain Research Bulletin.

[79]  Liping Huang,et al.  ZnT7, a Novel Mammalian Zinc Transporter, Accumulates Zinc in the Golgi Apparatus* , 2003, The Journal of Biological Chemistry.