Metal ions, Alzheimer's disease and chelation therapy

Ana Budimir 1
  • 1 Faculty of Pharmacy and Biochemistry, University of Zagreb, 10000 Zagreb, Croatia

Metal ions, Alzheimer's disease and chelation therapy

In the last few years, various studies have been providing evidence that metal ions are critically involved in the pathogenesis of major neurological diseases (Alzheimer, Parkinson). Metal ion chelators have been suggested as potential therapies for diseases involving metal ion imbalance. Neurodegeneration is an excellent target for exploiting the metal chelator approach to therapeutics. In contrast to the direct chelation approach in metal ion overload disorders, in neurodegeneration the goal seems to be a better and subtle modulation of metal ion homeostasis, aimed at restoring ionic balance. Thus, moderate chelators able to coordinate deleterious metals without disturbing metal homeostasis are needed. To date, several chelating agents have been investigated for their potential to treat neurodegeneration, and a series of 8-hydroxyquinoline analogues showed the greatest potential for the treatment of neurodegenerative diseases.

If the inline PDF is not rendering correctly, you can download the PDF file here.

  • D. M. Skovronsky, V. M.-Y. Lee and J. Q. Trojanowski, Neurodegenerative diseases: New concepts of pathogenesis and their therapeutic implications, Annu. Rev. Pathol. Mech. Dis. 1 (2006) 151-170; DOI: 10.1146/annurev.pathol.1.110304.100113.

  • R. Mayeux, Epidemiology of neurodegeneration, Annu. Rev. Neurosci. 26 (2003) 81-104; DOI: 10.1146/annurev.neuro.26.043002.094919.

  • C. P. Ferri, R. Sousa, E. Albanese, W. S. Ribeiro and M. Honyashiki, World Alzheimer Report 2009 - Executive Summary (Eds. M. Prince and J. Jadeson), Alzheimer's Disease International, London 2009, pp. 1-22; http://www.alz.co.uk/adi/publications.html

  • F. M. LaFerla and S. Oddo, Alzheimer's disease: Aβ, tau and synaptic dysfunction, Trends Mol. Med. 11 (2005) 170-176; DOI: 10.1016/j.molmed.2005.02.009.

  • M. Tolnay and A. Probst, Tau protein pathology in Alzheimer's disease and related disorders, Neuropathol. Appl. Neurobiol. 25 (1999) 171-187; DOI: 10.1046/j.1365-2990.1999.00182.x.

  • C. Ballatore, V. M.-Y. Lee and J. Q. Trojanowski, Tau-mediated neurodegeneration in Alzheimer's disease and related disorders, Nature Rev. Neurosci. 8 (2007) 663-672; DOI: 10.1038/nrn2194.

  • C. W. Scott, A. Fieles, L. A. Sygowski and C. B. Caputo, Aggregation of tau protein by aluminum, Brain Res. 628 (1993) 77-84; DOI: 10.1016/0006-8993(93)90940-O.

  • A. Yamamoto, R.-W. Shin, K. Hasegawa, H. Naiki, H. Sato, F. Yoshimasu and T. Kitamoto, Iron (III) induces aggregation of hyperphosphorylated tau, and its reduction to iron (II) reverses the aggregation: implications in the formation of neurofibrillary tangles of Alzheimer's disease, J. Neurochem. 86 (2003) 1137-1147; DOI: 10.1046/j.1471-4159.2002.01061.x.

  • R.-W. Shin, T. P. A. Kruck, H. Murayama and T. Kitamoto, A novel trivalent cation chelator Feralex dissociates binding of aluminum and iron associated with hyperphosphorylated tau of Alzheimer's disease, Brain Res. 961 (2003) 139-146; DOI: 10.1016/S0006-8993(02)03893-3.

  • T. Lührs, C. Ritter, M. Adrian, D. Riek-Loher, B. Bohrmann, H. Döbeli, D. Schubert and R. Riek, 3D structure of Alzheimer's amyloid-β (1-42) fibrils, Proc. Natl Acad. Sci. USA 102 (2005) 17342-17347; DOI: 10.1073/pnas.0506723102.

  • W. P. Esler and M. S. Wolfe, A portrait of Alzheimer secretases - new features and familiar faces, Science 293 (2001) 1449-1454; DOI: 10.1126/science.1064638.

  • M. P. Mattson, Pathways towards and away from Alzheimer's disease, Nature 430 (2004) 631-639; DOI: 10.1038/nature02621.

  • M. Shoji, T. Golde, J. Ghiso, T. Cheung, S. Estus, L. Shaffer, X. Cai, D. McKay, R. Tintner and B. Frangione, Production of the Alzheimer amyloid beta protein by normal proteolytic processing, Science 258 (1992) 126-129; DOI: 10.1126/science.1439760.

  • C. L. Masters, G. Simms, N. A. Weinman, G. Multhaup, B. L. McDonald and K. Beyreuther, Amyloid plaque core protein in Alzheimer disease and Down syndrome, Proc. Natl Acad. Sci. USA 82 (1985) 4245-4249; DOI: 10.1073/pnas.82.12.4245.

  • B. Clippingdale, J. D. Wade and C. J. Barrow, The amyloid-β peptide and its role in Alzheimer's disease, J. Peptide Sci. 7 (2001) 227-249; DOI: 10.1002/psc.324.abs.

  • C. Vigo-Pelfrey, D. Lee, P. Keim, I. Lieberburg and D. B. Schenk, Amyloid peptide from human cerebrospinal fluid, J. Neurochem. 61 (1993) 1965-1968; DOI: 10.1111/j.1471-4159.1993.tb09841.x.

  • P. Seubert, C. Vigo-Pelfrey, F. Esch, M. Lee, H. Dovey, D. Davis, S. Sinha, M. Schiossmacher, J. Whaley, C. Swindlehurst, R. McCormack, R. Wolfert, D. Selkoe, I. Lieberburg and D. Schenk, Isolation and quantification of soluble Alzheimer's β-peptide from biological fluids, Nature 359 (1992) 325-327; DOI: 10.1038/359325a0.

  • J. T. Jarret, E. P. Berger and P. T. Lansbury, The C-terminus of the β protein is critical in amyloidogenesis, Ann. NY Acad. Sci. USA 695 (1993) 144-148; DOI: 10.1111/j.1749-6632.1993.tb23043.x.

  • A. Lorenzo and B. A. Yankner, Beta-amyloid neurotoxicity requires fibril formation and is inhibited by congo red, Proc. Natl. Acad. Sci. USA 91 (1994) 12243-12247; DOI: 10.1073/pnas.91.25.12243.

  • J. Hardy and D. J. Selkoe, The amyloid hypothesis of Alzheimer's disease: Progress and problems on the road to therapeutics, Science 297 (2002) 353-356; DOI: 10.1126/science.1072994.

  • H. Kozlowski, A. Janicka-Klos, J. Brasun, E. Gaggelli, D. Valensin and G. Valensin, Copper, iron, and zinc ions homeostasis and their role in neurodegenerative disorders (metal uptake, transport, distribution and regulation), Coord. Chem. Rev. 253 (2009) 2665-2685; DOI: 10.1016/j.ccr.2009.05.011.

  • Y. Hung, A. Bush and R. Cherny, Copper in the brain and Alzheimer's disease, J. Biol. Inorg. Chem. 15 (2010) 61-76; DOI: 10.1007/s00775-009-0600-y.

  • P. J. Crouch, K. J. Barnham, A. I. Bush and A. R. White, Therapeutic Treatments for Alzheimer's disease based on metal bioavailability, Drug News Perspect. 19 (2006) 469-474; DOI: 10.1358/dnp.2006.19.8.1021492.

  • M. A. Lovell, J. D. Robertson, W. J. Teesdale, J. L. Campbell and W. R. Markesbery, Copper, iron and zinc in Alzheimer's disease senile plaques, J. Neurol. Sci. 158 (1998) 47-52; DOI: 10.1016/S0022-510X(98)00092-6.

  • C. S. Atwood, R. D. Moir, X. Huang, R. C. Scarpa, N. M. E. Bacarra, D. M. Romano, M. A. Hartshorn, R. E. Tanzi and A. I. Bush, Dramatic aggregation of Alzheimer Aβ by Cu(II) is induced by conditions representing physiological acidosis, J. Biol. Chem. 273 (1998) 12817-12826; DOI: 10.1074/jbc.273.21.12817.

  • B. Raman, T. Ban, K.-I. Yamaguchi, M. Sakai, T. Kawai, H. Naiki and Y. Goto, Metal ion-dependent effects of clioquinol on the fibril growth of an amyloid β peptide, J. Biol. Chem. 280 (2005) 16157-16162; DOI: 10.1074/jbc.M500309200.

  • P. Faller, Copper and zinc binding to amyloid-β: Coordination, dynamics, aggregation, reactivity and metal-ion transfer, ChemBioChem 10 (2009) 2837-2845; DOI: 10.1002/cbic.200900321.

  • C. Hureau and P. Faller, A[beta]-mediated ROS production by Cu ions: Structural insights, mechanisms and relevance to Alzheimer's disease, Biochimie 91 (2009) 1212-1217; DOI: 10.1016/j.biochi.2009.03.013.

  • M. A. Deibel, W. D. Ehmann and W. R. Markesbery, Copper, iron, and zinc imbalances in severely degenerated brain regions in Alzheimer's disease: possible relation to oxidative stress, J. Neurol. Sci. 143 (1996) 137-142; DOI: 10.1016/S0022-510X(96)00203-1.

  • M. C. Boll, M. Alcaraz-Zubeldia, S. Montes and C. Rios, Free copper, ferroxidase and SOD1 activities, lipid peroxidation and NO(x) content in the CSF. A different marker profile in four neurodegenerative diseases, Neurochem. Res. 33 (2008) 1717-1723; DOI: 10.1007/s11064-008-9610-3.

  • I. Maurer, S. Zierz and H. J. Moller, A selective defect of cytochrome c oxidase is present in brain of Alzheimer disease patients, Neurobiol. Aging 21 (2000) 455-462; DOI: 10.1016/S0197-4580(00) 00112-3.

  • Q. Ma, Y. Li, J. Du, H. Liu, K. Kanazawa, T. Nemoto, H. Nakanishi and Y. Zhao, Copper binding properties of a tau peptide associated with Alzheimer's disease studied by CD, NMR, and MALDI-TOF MS, Peptides 27 (2006) 841-849; DOI: 10.1016/j.peptides.2005.09.002.

  • N. T. Watt, I. J. Whitehouse and N. M. Hooper, The role of zinc in Alzheimer's disease, Int. J. Alzheimer's Dis. 2011 (2011) in press; DOI: 10.4061/2011/971021.

  • A. Bush, W. Pettingell, G. Multhaup, M. D. Paradis, J. Vonsattel, J. Gusella, K. Beyreuther, C. Masters and R. Tanzi, Rapid induction of Alzheimer A beta amyloid formation by zinc, Science 265 (1994) 1464-1467; DOI: 10.1126/science.8073293.

  • K. H. Lim, Y. K. Kim and Y.-T. Chang, Investigations of the molecular mechanism of metal-induced Aβ (1-40) amyloidogenesis, Biochemistry 46 (2007) 13523-13532; DOI: 10.1021/bi701112z.

  • C. Talmard, L. Guilloreau, Y. Coppel, H. Mazarguil, and P. Faller, Amyloid-beta peptide forms monomeric complexes with CuII and ZnII prior to aggregation, ChemBioChem 8 (2007) 163-165; DOI: 10.1002/cbic.200600319.

  • M. P. Cuajungco and K. Y. Faget, Zinc takes the center stage: its paradoxical role in Alzheimer's disease, Brain Res. Rev. 41 (2003) 44-56; DOI: 10.1016/S0165-0173(02)00219-9.

  • Z.-Y. Mo, Y.-Z. Zhu, H.-L. Zhu, J.-B. Fan, J. Chen and Y. Liang, Low micromolar zinc accelerates the fibrillization of human tau via bridging of Cys-291 and Cys-322, J. Biolog. Chem. 284 (2009) 34648-34657; DOI: 10.1074/jbc.M109.058883.

  • P. W. Mantyh, J. R. Ghilardi, S. Rogers, E. DeMaster, C. J. Allen, E. R. Stimson and J. E. Maggio, Aluminum, iron, and zinc ions promote aggregation of physiological concentrations of β-amyloid peptide, J. Neurochem. 61 (1993) 1171-1174; DOI: 10.1111/j.1471-4159.1993.tb03639.x.

  • C. Opazo, X. Huang, R. A. Cherny, R. D. Moir, A. E. Roher, A. R. White, R. Cappai, C. L. Masters, R. E. Tanzi, N. C. Inestrosa and A. I. Bush, Metalloenzyme-like activity of Alzheimer's disease β-amyloid, J. Biol. Chem. 277 (2002) 40302-40308; DOI: 10.1074/jbc.M206428200.

  • D. G. Smith, R. Cappai and K. J. Barnham, The redox chemistry of the Alzheimer's disease amyloid beta peptide, Biochim. Biophysi. Acta - Biomembranes 1768 (2007) 1976-1990; DOI: 10.2217/14796708.2.4.397.

  • P. F. Good, D. P. Perl, L. M. Bierer and J. Schmeidler, Selective accumulation of aluminum and iron in the neurofibrillary tangles of Alzheimer's disease: A laser microprobe (LAMMA) study, Ann. Neurol. 31 (1992) 286-292; DOI: 10.1002/ana.410310310.

  • I. Klatzo, H. Wisniewski and E. Streicher, Experimental production of neurofibrillary degeneration: 1. Light microscopic observations, J. Neuropathol. Exp. Neurol. 24 (1965) 187-199; DOI: 10.1097/00005072-196504000-00002.

  • R. D. Terry and C. Pena, Experimental production of neurofibrillary degeneration: 2. Electron microscopy, phosphatase histochemistry and electron prose analysis, J. Neuropathol. Exp. Neurol. 24 (1965) 200-210; DOI: 10.1097/00005072-196504000-00003.

  • D. Drago, M. Bettella, S. Bolognin, L. Cendron, J. Scancar, R. Milacic, F. Ricchelli, A. Casini, L. Messori, G. Tognon and P. Zatta, Potential pathogenic role of β-amyloid1-42-aluminum complex in Alzheimer's disease, Int. J. Biochem. Cell Biol. 40 (2008) 731-746; DOI: 10.1016/j.biocel.2007.10.014.

  • A. Rauk, The chemistry of Alzheimer's disease, Chem. Soc. Rev. 38 (2009) 2698-2715; DOI: 10.1039/b807980n.

  • L. E. Scott and C. Orvig, Medicinal inorganic chemistry approaches to passivation and removal of aberrant metal ions in disease, Chem. Rev. 109 (2009) 4885-4910; DOI: 10.1021/cr9000176.

  • J. A. Duce and A. I. Bush, Biological metals and Alzheimer's disease: Implications for therapeutics and diagnostics, Prog. Neurobiol. 92 (2010) 1-18; DOI: 10.1016/j.pneurobio.2010.04.003.

  • I. Bush and R. E. Tanzi, Therapeutics for Alzheimer's disease based on the metal hypothesis, Neurotherapeutics 5 (2008) 421-432; DOI: 10.1016/j.nurt.2008.05.001.

  • A. Gaeta and R. C. Hider, The crucial role of metal ions in neurodegeneration: the basis for a promising therapeutic strategy, Br. J. Pharmacol. 146 (2005) 1041-1059; DOI: 10.1038/sj.bjp.0706416.

  • P. Zatta, D. Drago, S. Bolognin and S. L. Sensi, Alzheimer's disease, metal ions and metal homeostatic therapy, Trends Pharmacol. Sci. 30 (2009) 346-355; DOI: 10.1016/j.tips.2009.05.002.

  • L. R. Perez and K. J. Franz, Minding metals: Tailoring multifunctional chelating agents for neurodegenerative disease, Dalton Trans. 39 (2010) 2177-2187; DOI: 10.1039/b919237a.

  • D. R. C. McLachlan, T. P. A. Kruck, W. Kalow, D. F. Andrews, A. J. Dalton, M. Y. Bell and W. L. Smith, Intramuscular desferrioxamine in patients with Alzheimer's disease, Lancet 337 (1991) 1304-1308; DOI: 10.1016/0140-6736(91)92978-B.

  • R. A. Cherny, J. T. Legg, C. A. McLean, D. P. Fairlie, X. Huang, C. S. Atwood, K. Beyreuther, R. E. Tanzi, C. L. Masters and A. I. Bush, Aqueous dissolution of Alzheimer's disease abeta amyloid deposits by biometal depletion, J. Biol. Chem. 274 (1999) 23223-23228; DOI: 10.1074/jbc.274.33.23223.

  • R. A. Cherny, K. J. Barnham, T. Lynch, I. Volitakis, Q.-X. Li, C. A. McLean, G. Multhaup, K. Beyreuther, R. E. Tanzi, C. L. Masters and A. I. Bush, Chelation and intercalation: Complementary properties in a compound for the treatment of Alzheimer's disease, J. Struct. Biol. 130 (2000) 209-216; DOI: 10.1006/jsbi.2000.4285.

  • C. Boldron, I. Van der Auwera, C. Deraeve, H. Gornitzka, S. Wera, M. Pitié, F. Van Leuven and B. Meunier, Preparation of cyclo-phen-type ligands: Chelators of metal ions as potential therapeutic agents in the treatment of neurodegenerative diseases, ChemBioChem 6 (2005) 1976-1980; DOI: 10.1002/cbic.200500220.

  • A. Dedeoglu, K. Cormier, S. Payton, K. A. Tseitlin, J. N. Kremsky, L. Lai, X. Li, R. D. Moir, R. E. Tanzi, A. I. Bush, N. W. Kowall, J. T. Rogers and X. Huang, Preliminary studies of a novel bifunctional metal chelator targeting Alzheimer's amyloidogenesis, Exp. Gerontol. 39 (2004) 1641-1649; DOI: 10.1016/j.exger.2004.08.016.

  • Z. Cui, P. R. Lockman, C. S. Atwood, C.-H. Hsu, A. Gupte, D. D. Allen and R. J. Mumper, Novel D-penicillamine carrying nanoparticles for metal chelation therapy in Alzheimer's and other CNS diseases, Eur. J. Pharm. Biopharm. 59 (2005) 263-272; DOI: 10.1016/j.ejpb.2004.07.009.

  • J.-Y. Lee, J. E. Friedman, I. Angel, A. Kozak and J.-Y. Koh, The lipophilic metal chelator DP-109 reduces amyloid pathology in brains of human [beta]-amyloid precursor protein transgenic mice, Neurobiol. Aging 25 (2004) 1315-1321; DOI: 10.1016/j.neurobiolaging.2004.01.005.

  • V. Moret, Y. Laras, N. Pietrancosta, C. Garino, G. Quelever, A. Rolland, B. Mallet, J. C. Norreel and J. L. Kraus, 1,1 '-Xylyl bis-1,4,8,11-tetraaza cyclotetradecane: A new potential copper chelator agent for neuroprotection in Alzheimer's disease. Its comparative effects with clioquinol on rat brain copper distribution, Bioorg. Med. Chem. Lett. 16 (2006) 3298-3301; DOI: 10.1016/j.bmcl.2006.03.026.

  • H. Zheng, S. Gal, L. M. Weiner, O. Bar-Am, A. Warshawsky, M. Fridkin and M. B. H. Youdim, Novel multifunctional neuroprotective iron chelator-monoamine oxidase inhibitor drugs for neurodegenerative diseases: in vitro studies on antioxidant activity, prevention of lipid peroxide formation and monoamine oxidase inhibition, J. Neurochem. 95 (2005) 68-78; DOI: 10.1111/j.1471-4159.2005.03340.x.

  • D. Kaur, F. Yantiri, S. Rajagopalan, J. Kumar, J. Q. Mo, R. Boonplueang, V. Viswanath, R. Jacobs, L. Yang, M. F. Beal, D. DiMonte, I. Volitaskis, L. Ellerby, R. A. Cherny, A. I. Bush and J. K. Andersen, Genetic or pharmacological iron chelation prevents MPTP-induced neurotoxicity in vivo: A novel therapy for Parkinson's disease, Neuron 37 (2003) 899-909; DOI: 10.1016/S0896-6273 (03)00126-0.

  • R. A. Cherny, C. S. Atwood, M. E. Xilinas, D. N. Gray, W. D. Jones, C. A. McLean, K. J. Barnham, I. Volitakis, F. W. Fraser, Y.-S. Kim, X. Huang, L. E. Goldstein, R. D. Moir, J. T. Lim, K. Beyreuther, H. Zheng, R. E. Tanzi, C. L. Masters and A. I. Bush, Treatment with a copper-zinc chelator markedly and rapidly inhibits [beta]-amyloid accumulation in Alzheimer's disease transgenic mice, Neuron 30 (2001) 665-676; DOI: 10.1016/S0896-6273(01)00317-8.

  • H. Zheng, M. B. H. Youdim, L. M. Weiner and M. Fridkin, Synthesis and evaluation of peptidic metal chelators for neuroprotection in neurodegenerative diseases, J. Pept. Res. 66 (2005) 190-203; DOI: 10.1111/j.1399-3011.2005.00289.x.

  • C. Deraeve, M. Pitie, H. Mazarguil and B. Meunier, Bis-8-hydroxyquinoline ligands as potential anti-Alzheimer agents, New J. Chem. 31 (2007) 193-195; DOI: 10.1039/b616085a.

  • C. W. Ritchie, A. I. Bush, A. Mackinnon, S. Macfarlane, M. Mastwyk, L. MacGregor, L. Kiers, R. Cherny, Q.-X. Li, A. Tammer, D. Carrington, C. Mavros, I. Volitakis, M. Xilinas, D. Ames, S. Davis, K. Beyreuther, R. E. Tanzi and C. L. Masters, Metal-protein attenuation with iodochlorhydroxyquin (clioquinol) targeting Aβ amyloid deposition and toxicity in Alzheimer disease: A pilot phase 2 clinical trial, Arch. Neurol. 60 (2003) 1685-1691; DOI: 10.1001/archneur.60.12.1685.

  • A. I. Bush, Metal complexing agents as therapies for Alzheimer's disease, Neurobiol. Aging 23 (2002) 1031-1038. DOI: 10.1016/S0197-4580(02)00120-3.

  • J. Tateishi, Subacute myelo-optico-neuropathy: Clioquinol intoxication in humans and animals, Neuropathology 20 (Suppl.) S20-S24; DOI: 10.1046/j.1440-1789.2000.00296.x.

  • M. S. Yassin, J. Ekblom, M. Xilinas, C. G. Gottfries and L. Oreland, Changes in uptake of vitamin B-12 and trace metals in brains of mice treated with clioquinol, J. Neurol. Sci 173 (2000) 40-44; DOI: 10.1016/S0022-510X(99)00297-X.

  • M. Di Vaira, C. Bazzicalupi, P. Orioli, L. Messori, B. Bruni and P. Zatta, Clioquinol, a drug for Alzheimer's disease specifically interfering with brain metal metabolism: Structural characterization of its zinc(II) and copper(II) complexes, Inorg. Chem. 43 (2004) 3795-3797; DOI: 10.1021/ic0494051.

  • C. C. Wagner, S. Calvo, M. H. Torre and E. J. Baran, Vibrational spectra of clioquinol and its Cu(II) complex, J. Raman Spectrosc. 38 (2007) 373-376; DOI: 10.1002/jrs.1654.

  • A. Budimir, N. Humbert, M. Elhabiri, I. Osinska, M. Birus and A.-M. Albrecht-Gary, Hydroxyquinoline based binders: Promising ligands for chelatotherapy?, J. Inorg. Biochem, in press; DOI: 10.1016/j.jinorgbio.2010.08.014.

  • R. A. Cherny, J. T. Legg, C. A. McLean, D. P. Fairlie, X. Huang, C. S. Atwood, K. Beyreuther, R. E. Tanzi, C. L. Masters and A. I. Bush, Aqueous dissolution of Alzheimer's disease Aβ amyloid deposits by biometal depletion, J. Biol. Chem. 274 (1999) 23223-23228; DOI: 10.1074/jbc.274.33.23223.

  • C. Grossi, S. Francese, A. Casini, M. C. Rosi, I. Luccarini, A. Fiorentini, C. Gabbiani, L. Messori, G. Moneti and F. Casamenti, Clioquinol decreases amyloid-β burden and reduces working memory impairment in a transgenic mouse model of Alzheimer's disease, J. Alzheimer's Dis. 17 (2009) 423-440.

  • L. Lannfelt, K. Blennow, H. Zetterberg, S. Batsman, D. Ames, J. Harrison, C. L. Masters, S. Targum, A. I. Bush, R. Murdoch, J. Wilson and C. W. Ritchie, Safety, efficacy, and biomarker findings of PBT2 in targeting Aβ as a modifying therapy for Alzheimer's disease: a phase IIa, double-blind, randomised, placebo-controlled trial, Lancet Neurol. 7 (2008) 779-786; DOI: 10.1016/S1474-4422(08)70167-4.

  • P. A. Adlard, R. A. Cherny, D. I. Finkelstein, E. Gautier, E. Robb, M. Cortes, I. Volitakis, X. Liu, J. P. Smith, K. Perez, K. Laughton, Q.-X. Li, S. A. Charman, J. A. Nicolazzo, S. Wilkins, K. Deleva, T. Lynch, G. Kok, C. W. Ritchie, R. E. Tanzi, R. Cappai, C. L. Masters, K. J. Barnham and A. I. Bush, Rapid restoration of cognition in Alzheimer's transgenic mice with 8-hydroxy quinoline analogs is associated with decreased interstitial Aβ, Neuron 59 (2008) 43-55; DOI: 10.1016/j.neuron.2008.06.018.

OPEN ACCESS

Journal + Issues

Search