Genetic Inhibition of Solute-Linked Carrier 39 Family Transporter 1 Ameliorates Aβ Pathology in a Model of Alzheimer's Disease
The aggregation or oligomerization of amyloid-β (Aβ) peptide is thought to be the primary causative event in the pathogenesis of Alzheimer's disease (AD). Considerable in vitro evidence indicates that the aggregation/oligomerization of Aβ is promoted in the presence of Zn; however, the functional role of Zn in AD pathogenesis is still not well clarified in vivo. Zn is imported into the brain mainly through the solute-linked carrier (Slc) 39 family transporters. Using a genetically tractable Drosophila model, we found that the expression of dZip1, the orthologue of human Slc39 family transporter hZip1 in Drosophila, was altered in the brains of Aβ42-expressing flies, and Zn homeostasis could be modulated by forcible dZip1 expression changes. An array of phenotypes associated with Aβ expression could be modified by altering dZip1 expression. Importantly, Aβ42 fibril deposits as well as its SDS-soluble form were dramatically reduced upon dZip1 inhibition, resulting in less neurodegeneration, significantly improved cognitive performance, and prolonged lifespan of the Aβ42-transgenic flies. These findings suggest that zinc contributes significantly to the Aβ pathology, and manipulation of zinc transporters in AD brains may provide a novel therapeutic strategy.
Vyšlo v časopise:
Genetic Inhibition of Solute-Linked Carrier 39 Family Transporter 1 Ameliorates Aβ Pathology in a Model of Alzheimer's Disease. PLoS Genet 8(4): e32767. doi:10.1371/journal.pgen.1002683
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1002683
Souhrn
The aggregation or oligomerization of amyloid-β (Aβ) peptide is thought to be the primary causative event in the pathogenesis of Alzheimer's disease (AD). Considerable in vitro evidence indicates that the aggregation/oligomerization of Aβ is promoted in the presence of Zn; however, the functional role of Zn in AD pathogenesis is still not well clarified in vivo. Zn is imported into the brain mainly through the solute-linked carrier (Slc) 39 family transporters. Using a genetically tractable Drosophila model, we found that the expression of dZip1, the orthologue of human Slc39 family transporter hZip1 in Drosophila, was altered in the brains of Aβ42-expressing flies, and Zn homeostasis could be modulated by forcible dZip1 expression changes. An array of phenotypes associated with Aβ expression could be modified by altering dZip1 expression. Importantly, Aβ42 fibril deposits as well as its SDS-soluble form were dramatically reduced upon dZip1 inhibition, resulting in less neurodegeneration, significantly improved cognitive performance, and prolonged lifespan of the Aβ42-transgenic flies. These findings suggest that zinc contributes significantly to the Aβ pathology, and manipulation of zinc transporters in AD brains may provide a novel therapeutic strategy.
Zdroje
1. HardyJSelkoeDJ 2002 Medicine - The amyloid hypothesis of Alzheimer's disease: Progress and problems on the road to therapeutics. Science 297 353 356
2. HardyJ 2006 A hundred years of Alzheimer's disease research. Neuron 52 3 13
3. WalshDMSelkoeDJ 2007 Abeta Oligomers - a decade of discovery. Journal of Neurochemistry 101 1172 1184
4. DanscherGJensenKBFredericksonCJKempKAndreasenA 1997 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. Journal of Neuroscience Methods 76 53 59
5. LovellMARobertsonJDTeesdaleWJCampbellJLMarkesberyWR 1998 Copper, iron and zinc in Alzheimer's disease senile plaques. Journal of the Neurological Sciences 158 47 52
6. FredericksonCJBushAI 2001 Synaptically released zinc: Physiological functions and pathological effects. Biometals 14 353 366
7. AtwoodCSMoirRDHuangXDScarpaRCBacarraNME 1998 Dramatic aggregation of Alzheimer Abeta by Cu(II) is induced by conditions representing physiological acidosis. Journal of Biological Chemistry 273 12817 12826
8. BushAIPettingellWHMulthaupGParadisMDVonsattelJP 1994 Rapid Induction of Alzheimer a-Beta Amyloid Formation by Zinc. Science 265 1464 1467
9. FredericksonCJKohJYBushAI 2005 The neurobiology of zinc in health and disease. Nature Reviews Neuroscience 6 449 462
10. StoltenbergMBushAIBachGSmidtKLarsenA 2007 Amyloid plaques arise from zinc-enriched cortical layers in APP/PS1 transgenic mice and are paradoxically enlarged with dietary zinc deficiency. Neuroscience 150 357 369
11. OpazoCHuangXDChernyRAMoirRDRoherAE 2002 Metalloenzyme-like activity of Alzheimer's disease beta-amyloid. Cu-dependent catalytic conversion of dopamine, cholesterol, and biological reducing agents to neurotoxic H2O2. Journal of Biological Chemistry 277 40302 40308
12. SamudralwarDLDipreteCCNiBFEhmannWDMarkesberyWR 1995 Elemental Imbalances in the Olfactory Pathway in Alzheimers-Disease. Journal of the Neurological Sciences 130 139 145
13. DeibelMAEhmannWDMarkesberyWR 1996 Copper, iron, and zinc imbalances in severely degenerated brain regions in Alzheimer's disease: Possible relation to oxidative stress. Journal of the Neurological Sciences 143 137 142
14. CornettCRMarkesberyWREhmannWD 1998 Imbalances of trace elements related to oxidative damage in Alzheimer's disease brain. Neurotoxicology 19 339 345
15. MantyhPWGhilardiJRRogersSDemasterEAllenCJ 1993 Aluminum, Iron, and Zinc Ions Promote Aggregation of Physiological Concentrations of Beta-Amyloid Peptide. Journal of Neurochemistry 61 1171 1174
16. BushAIMoirRDRosenkranzKMTanziRE 1995 Zinc and Alzheimers-Disease - Response. Science 268 1921 1923
17. ClementsAAllsopDWalshDMWilliamsCH 1996 Aggregation and metal-binding properties of mutant forms of the amyloid Abeta peptide of Alzheimer's disease. Journal of Neurochemistry 66 740 747
18. EslerWPStimsonERJenningsJMGhilardiJRMantyhPW 1996 Zinc-induced aggregation of human and rat beta-amyloid peptides in vitro. Journal of Neurochemistry 66 723 732
19. ChernyRAAtwoodCSXilinasMEGrayDNJonesWD 2001 Treatment with a copper-zinc chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer's disease transgenic mice. Neuron 30 665 676
20. WhiteARDuTLaughtonKMVolitakisISharplesRA 2006 Degradation of the Alzheimer disease amyloid beta-peptide by metal-dependent up-regulation of metalloprotease activity. Journal of Biological Chemistry 281 17670 17680
21. DonnellyPSCaragounisADuTLaughtonKMVolitakisI 2008 Selective intracellular release of copper and zinc ions from bis(thiosemicarbazonato) complexes reduces levels of Alzheimer disease amyloid-beta peptide. Journal of Biological Chemistry 283 4568 4577
22. LiCWangJZhouB 2010 The metal chelating and chaperoning effects of clioquinol: insights from yeast studies. Journal of Alzheimer's Disease 21 1249 1262
23. CousinsRJLiuzziJPLichtenLA 2006 Mammalian zinc transport, trafficking, and signals. Journal of Biological Chemistry 281 24085 24089
24. LichtenLACousinsRJ 2009 Mammalian Zinc Transporters: Nutritional and Physiologic Regulation. Annual Review of Nutrition 29 153 176
25. WangXXZhouB 2010 Dietary Zinc Absorption: A Play of Zips and ZnTs in the Gut. Iubmb Life 62 176 182
26. HuangLPKirschkeCPZhangYFYuYY 2005 The ZIP7 gene (Slc39a7) encodes a zinc transporter involved in zinc homeostasis of the Golgi apparatus. Journal of Biological Chemistry 280 15456 15463
27. IijimaKLiuHPChiangASHearnSAKonsolakiM 2004 Dissecting the pathological effects of human Abeta40 and Abeta42 in Drosophila: A potential model for Alzheimer's disease. Proceedings of the National Academy of Sciences of the United States of America 101 6623 6628
28. FinelliAKelkarASongHJYangHDKonsolakiM 2004 A model for studying Alzheimer's Abeta 42-induced toxicity in Drosophila melanogaster. Molecular and Cellular Neuroscience 26 365 375
29. TullyTQuinnWG 1985 Classical-Conditioning and Retention in Normal and Mutant Drosophila-Melanogaster. Journal of Comparative Physiology A: Sensory Neural and Behavioral Physiology 157 263 277
30. WalshDMSelkoeDJ 2007 Aβ oligomers—a decade of discovery. J Neurochem 101 1172 1184
31. FarrisWMansourianSChangYLindsleyLEckmanEA 2003 Insulin-degrading enzyme regulates the levels of insulin, amyloid b-protein, and the b-amyloid precursor protein intracellular domain in vivo. Proc Natl Acad Sci USA 100 4162 4167
32. IwataNTsubukiSTakakiYWatanabeKSekiguchiM 2003 Identification of the major Abeta1-42-degrading catabolic pathway in brain parenchyma: suppression leads to biochemical and pathological deposition. Nat Med 6 2 143 150
33. FredericksonCJSuhSWSilvaDFredericksonCJThompsonRB 2000 Importance of zinc in the central nervous system: The zinc-containing neuron. Journal of Nutrition 130 1471s 1483s
34. SuhSWJensenKBJensenMSSilvaDSKesslakPJ 2000 Histochemically-reactive zinc in amyloid plaques, angiopathy, and degenerating neurons of Alzheimer's diseased brains. Brain Research 852 274 278
35. BeyerNCoulsonDTRHeggartySRavidRIrvineGB 2009 ZnT3 mRNA levels are reduced in Alzheimer's disease post-mortem brain. Molecular Neurodegeneration 4 53 62
36. AdlardPAParncuttJMFinkelsteinDIBushAI 2010 Cognitive Loss in Zinc Transporter-3 Knock-Out Mice: A Phenocopy for the Synaptic and Memory Deficits of Alzheimer's Disease? Journal of Neuroscience 30 1631 1636
37. IijimaKChiangHCHearnSAHakkerIGattA 2008 Abeta 42 Mutants with Different Aggregation Profiles Induce Distinct Pathologies in Drosophila. PLoS ONE 3 e1703 doi:10.1371/journal.pone.0001703
38. ChiangHCWangLXieZLYauAZhongY 2010 PI3 kinase signaling is involved in Abeta-induced memory loss in Drosophila. Proceedings of the National Academy of Sciences of the United States of America 107 7060 7065
39. LeeYSCarthewRW 2003 Making a better RNAi vector for Drosophila: use of intron spacers. Methods 30 322 329
40. JinPZarnescuDCZhangFPPearsonCELucchesiJC 2003 RNA-mediated neurodegeneration caused by the fragile X premutation rCGG repeats in Drosophila. Neuron 39 739 747
41. TullyTPreatTBoyntonSCDelvecchioM 1994 Genetic Dissection of Consolidated Memory in Drosophila. Cell 79 35 47
42. CoylePZalewskiPDPhilcoxJCForbesIJWardAD 1994 Measurement of zinc in hepatocytes by using a fluorescent probe, Zinquin: relationship to metallothionein and intracellular zinc. Biochemical Journal 303 781 786
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
2012 Číslo 4
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