, Volume 1, Issue 1, pp 117–127 | Cite as

Neuroprotective strategies in Alzheimer’s disease



In addition to strategies designed to decrease amyloid beta (Aβ) levels, it is likely that successful Alzheimer’s disease (AD) therapeutic regimens will require the concomitant application of neuroprotective agents. Elucidation of pathophysiological processes occurring in AD and identification of the molecular targets mediating these processes point to potential high-yield neuroprotective strategies. Candidate neuroprotective agents include those that interact specifically with neuronal targets to inhibit deleterious intraneuronal mechanisms triggered by Aβ and other toxic stimuli. Strategies include creating small molecules that block Aβ interactions with cell surface and intracellular targets, down-regulate stress kinase signaling cascades, block activation of caspases and expression of pro-apoptotic proteins, and inhibit enzymes mediating excessive tau protein phosphorylation. Additional potential neuroprotective compounds include those that counteract loss of cholinergic function, promote the trophic state and plasticity of neurons, inhibit accumulation of reactive oxygen species, and block excitotoxicity. Certain categories of compounds, such as neurotrophins or neurotrophin small molecule mimetics, have the potential to alter neuronal signaling patterns such that several of these target actions might be achieved by a single agent.

Key Words

Alzheimer neuroprotection amyloid stress kinase neurotrophin 


  1. 1.
    Golde TE. Alzheimer disease therapy: can the amyloid cascade be halted?J Clin Invest 111: 11–18, 2003.PubMedGoogle Scholar
  2. 2.
    Selkoe DJ, Schenk D. Alzheimer’s disease: molecular understanding predicts amyloid-based therapies.Annu Rev Pharmacol Toxicol 43: 545–584, 2003.PubMedGoogle Scholar
  3. 3.
    Golde TE. Inflammation takes on Alzheimer disease.Nat Med 8: 936–938, 2002.PubMedGoogle Scholar
  4. 4.
    McGeer PL, McGeer EG. Local neuroinflammation and the progression of Alzheimer’s disease.J Neurovirol 8: 529–538, 2002.PubMedGoogle Scholar
  5. 5.
    Brookmeyer R, Gray S, Kawas C. Projections of Alzheimer’s disease in the United States and the public health impact of delaying disease onset.Am J Public Health 88: 1337–1342, 1998.PubMedGoogle Scholar
  6. 6.
    Hake AM, Scherer P. On the brink of the pandemic: epidemiology and risk factors for Alzheimer’s. Paper presented at the World Alzheimer’s Congress, Washington, D.C., July 9–18, 2000.Google Scholar
  7. 7.
    Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics.Science 297: 353–356, 2002.PubMedGoogle Scholar
  8. 8.
    Holtzman DM, Bales KR, Paul SM, DeMattos RB. Aβ immunization and anti-Aβ antibodies: potential therapies for the prevention and treatment of Alzheimer’s disease.Adv Drug Delivery Rev 54: 1603–1613, 2002.Google Scholar
  9. 9.
    Smith MA, Casadesus G, Joseph JA, Perry G. Amyloid-β and τ serve antioxidant functions in the aging and Alzheimer brain.Free Radic Biol Med 9: 1194–1199, 2002.Google Scholar
  10. 10.
    Plant LD, Boyle JP, Smith IF, Peers C, Pearson HA. The production of amyloid β peptide is a critical requirement for the viability of central neurons.J Neurosci 23: 5531–5535, 2003.PubMedGoogle Scholar
  11. 11.
    Yankner BA. The pathogenesis of Alzheimer’s disease. Is amyloid β-protein the beginning of the end?Ann NY Acad Sci 924: 26–28, 2000.PubMedGoogle Scholar
  12. 12.
    Yankner BA, Caceres A, Duffy LK. Nerve growth factor potentiates the neurotoxicity of β-amyloid.Proc Natl Acad Sci USA 87: 9020–9023, 1990.PubMedGoogle Scholar
  13. 13.
    Takahashi RH, Milner TA, Li F, Nam EE, Edgar MA, Yamaguchi H et al. Intraneuronal Alzheimer Aβ42 accumulates in multivesicular bodies and is associated with synaptic pathology.Am J Path 161: 1869–1879, 2002.PubMedGoogle Scholar
  14. 14.
    Zhang Y, McLaughlin R, Goodyer C, LeBlanc A. Selective cytotoxicity of intracellular amyloid β peptide 1–41 through p53 and Bax in cultured primary human neurons.J Cell Biol 156: 519–529, 2002.PubMedGoogle Scholar
  15. 15.
    Kawasumi M, Hashimoto Y, Chiba T, Kanekura K, Yamagishi Y, Ishizaka M et al. Molecular mechanisms for neuronal cell death by Alzheimer’s amyloid precursor protein-relevant insults.Neurosignals 11: 236–250, 2002.PubMedGoogle Scholar
  16. 16.
    Tran MH, Yamada K, Nabeshima T. Amyloid β-peptide induces cholinergic dysfunction and cognitive deficits: a minireview.Peptides 23: 1271–1283, 2002.PubMedGoogle Scholar
  17. 17.
    Bozyczko-Coyne D, O’Kane TM, Wu ZL, Dobrzanski P, Murthy S, Vaught JL, Scott RW. CEP-1347/KT-7515, as an inhibitor of SAPK/JNK pathway activation, promotes survival and blocks multiple events associated with Aβ-induced cortical neuron apoptosis.J Neurochem 77: 849–863, 2001.PubMedGoogle Scholar
  18. 18.
    Bozyczko-Coyne D, Saporito MS, Hudkins RL. Targeting the JNK pathway for therapeutic benefit in CNS disease.Curr Drug Target CNS Neurol Disord 1: 31–49, 2002.Google Scholar
  19. 19.
    Morishima Y, Gotoh Y, Zieg J, Barrett T, Takano H, Flavell R, Davis RJ, Shirasaki Y, Greenberg ME. β-amyloid induces neuronal apoptosis via a mechanism that involves the c-Jun N-terminal kinase pathway and the induction of Fas ligand.J Neurosci 21: 7551–7560, 2001.PubMedGoogle Scholar
  20. 20.
    Fogarty MP, Downer EJ, Campbell V. A role for c-Jun N-terminal kinase 1 (JNK1), but not JNK2, in the β-amyloid-mediated stabilization of protein p53 and induction of the apoptotic cascade in cultured cortical neurons.Biochem J 371: 789–798, 2003.PubMedGoogle Scholar
  21. 21.
    Shoji M, Iwakami N, Takeuchi S, Waragai M, Suzuki M, Kanazawa I, Lippa CF, Ono S, Okazawa H. JNK activation is associated with intracellular β-amyloid accumulation.Brain Res Mol Brain Res 85: 221–233, 2000.PubMedGoogle Scholar
  22. 22.
    Zhu X, Raina AK, Rottkamp CA, Aliev G, Peggy G, Boux H, Smith MA. Activation and redistribution of c-Jun N-terminal kinase/stress activated protein kinase in degenerating neurons in Alzheimer’s disease.J Neurochem 76: 435–441, 2001.PubMedGoogle Scholar
  23. 23.
    Pei JJ, Braak E, Braak H, Grundke-Iqbal I, Iqbal K, Winbald B, Cowburn RF. Localization of active forms of C-jun kinase (JNK) and p38 kinase in Alzheimer’s disease brains at different stages of neurofibrillary degeneration.J Alzheimers Dis 3: 41–48, 2001.PubMedGoogle Scholar
  24. 24.
    Savage MJ, Lin YG, Ciallella JR, Flood DG, Scott RW. Activation of c-Jun N-terminal kinase and p38 in an Alzheimer’s disease model is associated with amyloid deposition.J Neurosci 22: 3376–3385, 2002.PubMedGoogle Scholar
  25. 25.
    Troy CM, Rabacchi SA, Xu Z, Maroney AC, Connors TJ, Shelanski ML, Greene LA. β-Amyloid-induced neuronal apoptosis requires c-Jun N-terminal kinase activation.J Neurochem 77: 157–164, 2001.PubMedGoogle Scholar
  26. 26.
    Wei W, Wang X, Kusiak JW. Signaling events in amyloid β-peptide-induced neuronal death and insulin growth factor I protection.J Biol Chem 277: 17649–17656, 2002.PubMedGoogle Scholar
  27. 27.
    Marques CA, Keil U, Bonert A, Steiner B, Hass C, Muller WE, Eckert A. Neurotoxic mechanisms caused by the Alzheimer’s disease-linked Swedish APP mutation: oxidative stress, caspases and JNK pathway.J Biol Chem 278: 28294–28302, 2003.PubMedGoogle Scholar
  28. 28.
    Tamagno E, Robino G, Obbili A, Bardini P, Aragno M, Parola M et al. H2O2 and 4-hydroxynonenal mediate amyloid β-induced neuronal apoptosis by activating JNKs and p38MAPK.Exp Neurol 180: 144–155, 2003.PubMedGoogle Scholar
  29. 29.
    Harris CA, Deshmukh M, Tsui-Pierchala B, Maroney AC, Johnson EM. Inhibition of the c-Jun N-terminal kinase signaling pathway by the mixed lineage kinase inhibitor CEP-1347 preserves metabolism and growth of trophic factor-deprived neurons.J Neurosci 22: 103–113, 2002.PubMedGoogle Scholar
  30. 30.
    Trojanowski JQ, Lee VM. The role of tau in Alzheimer’s disease.Med Clin North Am 86: 615–627, 2002.PubMedGoogle Scholar
  31. 31.
    Alvarez G, Munoz-Montano JR, Satrustegui J, Avila J, Bogonez E, Diaz-Nido J. Regulation of tau phosphorylation and protection against β-amyloid-induced neurodegeneration by lithium. Possible implications for Alzheimer’s disease.Bipolar Disorder 4: 153–165, 2002.Google Scholar
  32. 32.
    Gozes I. Tau as a drug target in Alzheimer’s disease.J Mol Neurosci 19: 337–338, 2002.PubMedGoogle Scholar
  33. 33.
    Chen G, Huang LD, Jiang YM, Manji HK. The mood-stabilizing agent valproate inhibits the activity of glycogen synthase kinase-3.J Neurochem 72: 1327–1330, 1999.PubMedGoogle Scholar
  34. 34.
    Loy R, Tariot PN. Neuroprotective properties of valproate: potential benefit for AD and tauopathies.J Mol Neurosci 19: 303–307, 2002.PubMedGoogle Scholar
  35. 35.
    Sato S, Tatebayashi Y, Akagi T, Chui DH, Murayama M, Miyasaka T et al. Aberrant tau phosphorylation by glycogen synthase kinase-3β and JNK3 induces oligomeric tau fibrils in COS-7 cells.J Biol Chem 277: 42060–42065, 2002.PubMedGoogle Scholar
  36. 36.
    Michaelis ML, Chen Y, Hill S, Reiff E, Georg G, Rice A, Audus K. Amyloid peptide toxicity and microtubule-stabilizing drugs.J Mol Neurosci 19: 101–105, 2002.PubMedGoogle Scholar
  37. 37.
    Roth KA. Caspases, apoptosis, and Alzheimer disease: causation, correlation, and confusion.J Neuropathol Exp Neurol 60: 829–838, 2001.PubMedGoogle Scholar
  38. 38.
    Rohn TT, Rissman RA, Head E, Cotman CW. Caspase activation in the Alzheimer’s disease brain: tortuous and torturous.Drug News Perspect 15: 549–557, 2002.PubMedGoogle Scholar
  39. 39.
    Yuan J, Yankner BA. Apoptosis in the nervous system.Nature 407: 802–809, 2000.PubMedGoogle Scholar
  40. 40.
    Ivins KJ, Thornton PL, Rohn TT, Cotman CW. Neuronal apoptosis induced by β-amyloid is mediated by caspase-8.Neurobiol Dis 6: 440–449, 1999.PubMedGoogle Scholar
  41. 41.
    Allen JW, Eldadah BA, Huang X, Knoblach SM, Faden AI. Multiple caspases are involved in β-amyloid-induced neuronal apoptosis.J Neurosci Res 65: 45–53, 2001.PubMedGoogle Scholar
  42. 42.
    Deshmukh M, Vasilakos J, Deckwerth TL, Lampe PA, Shivers BD, Johnson EM Jr. Genetic and metabolic status of NGF-deprived sympathetic neurons saved by an inhibitor of ICE family proteases.J Cell Biol 135: 1341–1354, 1996.PubMedGoogle Scholar
  43. 43.
    Dore S, Kar S, Quirion R. Insulin-like growth factor I protects and rescues hippocampal neurons against β-amyloid- and human amylin-induced toxicity.Proc Natl Acad Sci 94: 4772–4777, 1997.PubMedGoogle Scholar
  44. 44.
    Mattson MR, Tomaselli K, Rydel RE. Calcium-destabilizing and neurodegenerative effects of aggregated β-amyloid peptide are attenuated by basic FGF.Brain Res 1993a;621: 35–49, 1997.Google Scholar
  45. 45.
    Fitzpatrick JL, Mize AL, Wade CB, Harris JA, Shapiro RA, Dorsa DM. Estrogen-mediated neuroprotection against β-amyloid toxicity requires expression of estrogen receptor α orβ and activation of the MAPK pathway.J Neurochem 82: 674–682, 2002.PubMedGoogle Scholar
  46. 46.
    Gozes I, Brenneman DE. A new concept in the pharmacology of neuroprotection.J Mol Neurosci 14: 61–68, 2000.PubMedGoogle Scholar
  47. 47.
    Niikura T, Hashimoto Y, Tajima H, Nishimoto I. Death and survival of neuronal cells exposed to Alzheimer’s insults.J Neurosci Res 70: 380–391, 2002.PubMedGoogle Scholar
  48. 48.
    Vicario-Abejon C, Owens D, McKay R, Segal M. Role of neurotrophins in central synapse formation and stabilization.Nat Rev Neurosci 3: 965–974, 2002.PubMedGoogle Scholar
  49. 49.
    Selkoe DJ. Alzheimer’s disease is a synaptic failure.Science 298: 789–791, 2002.PubMedGoogle Scholar
  50. 50.
    Sofroniew MV, Howe CL, Mobley WC. Nerve growth factor signaling, neuroprotection, and neural repair.Annu Rev Neurosci 24: 1217–1281, 2001.PubMedGoogle Scholar
  51. 51.
    Chao MV. Neurotrophins and their receptors: a convergence point for many signaling pathways.Nature Rev 4: 299–309, 2003.Google Scholar
  52. 52.
    Mufson EJ, Kordower JH. Cortical neurons express nerve growth factor receptors in advanced age and Alzheimer’s disease.Proc Natl Acad Sci 89: 569–573, 1992.PubMedGoogle Scholar
  53. 53.
    Drake CT, Milner TA, Patterson SL. Ultrastructural localization of full-length trkB immunoreactivity in rat hippocampus suggests multiple roles in modulating activity-dependent synaptic plasticity.J Neurosci 19: 8009–8026, 1999.PubMedGoogle Scholar
  54. 54.
    Savaskan E, Muller-Spahn F, Olivieri G, Bruttel S, Otten U, Rosenberg C, Hulette C, Hock C. Alterations in trkA, trkB and trk C receptor immunoreactivities in parietal cortex and cerebellum in Alzheimer’s disease.Eur Neurol 44: 172–180, 2000.PubMedGoogle Scholar
  55. 55.
    Pitts AF, Miller MW. Expression of nerve growth factor, brain-derived neurotrophic factor, and neurotrophin-3 in the somatosensory cortex of the mature rat: coexpression with high-affinity neurotrophin receptors.J Comp Neurol 418: 241–254, 2000.PubMedGoogle Scholar
  56. 56.
    Hu X-Y, Zhang H-Y, Qin S, Xu H, Swaab DF, Zhou J-N. Increased p75NTR expression in hippocampus neurons containing hyperphosphorylated τ in Alzheimer patients.Exp Neurol 178: 104–111, 2002.PubMedGoogle Scholar
  57. 57.
    Park H-S, Kim M-S, Huh S-H, Park J, Chung J, Kang SS, Choi E-J. Akt (protein kinase B) negatively regulates SEK1 by means of protein phosphorylation.J Biol Chem 277: 2573–2578, 2002.PubMedGoogle Scholar
  58. 58.
    Dugan LL, Creedon DJ, Johnson EM, Holtzman DM. Rapid suppression of free radical formation by nerve growth factor involves the mitogen-activated protein kinase pathway.Proc Natl Acad Sci USA 94: 4086–4091, 1997.PubMedGoogle Scholar
  59. 59.
    Roux PP, Barker PA. Neurotrophin signaling through the p75 neurotrophin receptor.Prog Neurobiol 67: 203–233, 2002.PubMedGoogle Scholar
  60. 60.
    Rabizadeh S, Bredesen DE. Ten years on: mediation of cell death by the common neurotrophin receptor p75NTR.Cytokine Growth Factor Rev 14: 224–239, 2003.Google Scholar
  61. 61.
    Dobrowsky RT, Carter BD. Coupling of the p75 neurotrophin receptor to sphingolipid signaling.Ann NY Acad Sci 845: 32–45, 1998.PubMedGoogle Scholar
  62. 62.
    Fahnestock M, Michalski B, Xu B, Coughlin MD. The precursor pro-nerve growth factor is the predominant form of nerve growth factor in brain and is increased in Alzheimer’s disease.Mol Cell Neurosci 18: 210–220, 2001.PubMedGoogle Scholar
  63. 63.
    Hempstead BL. The many faces of p75NTR.Curr Opin Neurobiol 12: 260–267, 2002.PubMedGoogle Scholar
  64. 64.
    Longo, FM, Manthorpe M, Xie Y, Varon S. Synthetic NGF peptide derivatives prevent neuronal death via a p75 receptor-dependent mechanism.J Neurosci Res 48: 1–17, 1997.PubMedGoogle Scholar
  65. 65.
    Tuszynski MH. Growth-factor gene therapy for neurodegenerative disorders.Lancet Neurol 1: 51–57, 2002.PubMedGoogle Scholar
  66. 66.
    Robner S, Ueberham U, Schliebs R, Perez-Polo JR, Bigl V. The regulation of amyloid precursor protein metabolism by cholinergic mechanisms and neurotrophin receptor signaling.Prog Neurobiol 56: 541–569, 1998.Google Scholar
  67. 67.
    Mufson EJ, Kroin JS, Sendera TJ, Sobreviela T. Distribution and retrograde transport of trophic factors in the central nervous system: functional implications for the treatment of neurodegenerative diseases.Prog Neurobiol 57: 451–484, 1999.PubMedGoogle Scholar
  68. 68.
    Cooper JD, Salehi A, Delcroix JD, Howe CL, Belichenko PV, Chua-Couzens J et al. Failed retrograde transport of NGF in a mouse model of Down syndrome: reversal of cholinergic neurodegenerative phenotype following NGF infusion.Proc Natl Acad Sci USA 98: 10439–10444, 2001.PubMedGoogle Scholar
  69. 69.
    Salehi A, Delcroix JD, Mobley WC. Traffic at the intersection of neurotrophic factor signaling and neurodegeneration.Trends Neurosci 26: 73–80, 2003.PubMedGoogle Scholar
  70. 70.
    Capsoni S, Giannotta S, Cattaneo A. β-amyloid plaques in a model for sporadic Alzheimer’s disease based on transgenic anti-nerve growth factor antibodies.Mol Cell Neurosci 21: 15–28, 2002.PubMedGoogle Scholar
  71. 71.
    Pizzo DP, Winkler J, Sidiqi I, Waite JJ, Thal LJ. Modulation of sensory inputs and ectopic presence of Schwann cells depend upon the route and duration of nerve growth factor administration.Exp Neurol 178: 91–103, 2002.PubMedGoogle Scholar
  72. 72.
    Eriksdotter JM, Nordberg A, Amberla K, Backman L, Ebendal T, Meyerson B, Olson L et al. Intracerebroventricular infusion of nerve growth factor in three patients with Alzheimer’s disease.Dement Geriatr Cogn Disord 9: 246–257, 1998.Google Scholar
  73. 73.
    Xie Y, Longo FM. Neurotrophin small-molecule mimetics.Prog Brain Res 128: 333–347, 2000.PubMedGoogle Scholar
  74. 74.
    Saragovi HU, Gehring K. Development of pharmacological agents for targeting neurotrophins and their receptors.Trends Pharmacol Sci 21: 93–98, 2000.PubMedGoogle Scholar
  75. 75.
    Massa SM, Xie YM, Longo FM. Alzheimer’s therapeutics: neurotrophin small molecule mimetics.J Mol Neurosci 19: 107–111, 2002.PubMedGoogle Scholar
  76. 76.
    Xie Y, Tisi MA, Yeo TT, Longo FM. Nerve growth factor (NGF) loop 4 dimeric mimetics activate ERK and AKT and promote NGF-like neurotrophic effects.J Biol Chem 275: 29868–29874, 2000.PubMedGoogle Scholar
  77. 77.
    Auld DA, Kornecook TJ, Bastianetto S, Quirion R. Alzheimer’s disease and the basal forebrain cholinergic system: relations to β-amyloid peptides, cognition, and treatment strategies.Prog Neurobiol 68: 209–245, 2002.PubMedGoogle Scholar
  78. 78.
    Farlow M, Anand R, Messina J Jr, Hartman R, Veach J. A 52-week study of the efficacy of rivastigmine in patients with mild to moderately severe Alzheimer’s disease.Eur Neurol 44: 236–241, 2000.PubMedGoogle Scholar
  79. 79.
    Coyle J, Kershaw P. Galantamine, a cholinesterase inhibitor that allosterically modulates nicotinic receptors: effects on the course of Alzheimer’s disease.Biol Psychiatry 49: 289–299, 2001.PubMedGoogle Scholar
  80. 80.
    Doraiswamy PM, Krishnan KR, Anand R, Sohn H, Danyluk J, Hartman RD, Veach J. Long-term effects of rivastigmine in moderately severe Alzheimer’s disease: does early initiation of therapy offer sustained benefits?Prog Neuropsychopharmacol Biol Psychiatry 26: 705–712, 2002.PubMedGoogle Scholar
  81. 81.
    Farlow M, Potkin S, Koumaras B, Veach J, Mirski D. Analysis of outcome in retrieved dropout patients in a rivastigmine vs placebo, 26-week, Alzheimer disease trial.Arch Neurol 60: 843–848, 2003.PubMedGoogle Scholar
  82. 82.
    Fisher A, Brandeis R, Haring R, Kliger-Spatz M, Natan N, Sonego H et al. AF150(S) and AF267B: M1 muscarinic agonists as innovative therapies for Alzheimer’s disease.J Mol Neurosci 19: 145–153, 2002.PubMedGoogle Scholar
  83. 83.
    Nitsch RM, Slack BE, Wurtman RJ, Growdon JH. Release of Alzheimer amyloid precursor derivatives stimulated by activation of muscarinic acetylcholine receptors.Science 258: 304–307, 1992.PubMedGoogle Scholar
  84. 84.
    Buxbaum JD, Oishi M, Chen HI, Pinkas-Kramarski R, Jaffe EA, Gandy SE, Greengard P. Cholinergic agonists and interleukin 1 regulate processing and secretion of the Alzheimer beta-A4 amyloid protein precursor.Proc Natl Acad Sci USA 89: 10075–10078, 1992.PubMedGoogle Scholar
  85. 85.
    Hung AY, Haass C, Nitsch RM, Qui WQ, Citron M, Wurtman RJ, Growdon JH, Selkoe DJ. Activation of protein kinase C inhibits cellular production of the amyloid beta-protein.J Biol Chem 268: 22959–22962, 1993.PubMedGoogle Scholar
  86. 86.
    Lin L, Georgievska B, Mattson A, Isacson O. Cognitive changes and modified processing of amyloid precursor protein in the cortical and hippocampal system after cholinergic synapse loss and muscarinic receptor activation.Proc Natl Acad Sci USA 96: 12108–12113, 1999.PubMedGoogle Scholar
  87. 87.
    Hellstrom-Lindahl E. Modulation of β-amyloid precursor protein processing and tau phosphorylation by acetylcholine receptors.Eur J Pharmacol 393: 255–263, 2000.PubMedGoogle Scholar
  88. 88.
    Kihara T, Shimohama S, Sawada H, Honda K, Nakamizo T, Shibasaki H, Kume T, Akaike A. α7 Nicotinic receptor transduces signals to phosphatidylinositol 3-kinase to block Aβ-amyloid-induced neurotoxicity.J Biol Chem 276: 13541–13546, 2001.PubMedGoogle Scholar
  89. 89.
    Knipper M, de Penha Berzaghi M, Blochl A, Breer H, Thoenen H, Lindholm D. Positive feedback between acetylcholine and the neurotrophins nerve growth factor and brain-derived growth neurotrophic factor in the rat hippocampus.Eur J Neurosci 6: 668–671, 1994.PubMedGoogle Scholar
  90. 90.
    Isacson O, Seo H, Lin L, Albeck D, Granholm AC. Alzheimer’s disease and Down’s syndrome: roles of APP, trophic factors and Ach.Trends Neurosci 25: 79–84, 2002.PubMedGoogle Scholar
  91. 91.
    Nitsch RM, Deng M, Tennis M, Schoenfeld D, Growdon JH. The selective muscarinic M1 agonist AF102B decreases levels of total Aβ in cerebrospinal fluid of patients with Alzheimer’s disease.Ann Neurol 48: 913–918, 2000.PubMedGoogle Scholar
  92. 92.
    Hock C, Maddalena A, Raschig A, Muller-Spahn F, Eschweiler G, Hag K et al. Treatment with the selective muscarinic m1 agonist talsaclidin decreases cerebrospinal fluid levels of Aβ42 in patients with Alzheimer’s disease.Amyloid 10: 1–6, 2003.PubMedGoogle Scholar
  93. 93.
    Butterfield DA. Amyloid β-peptide (1–42)-induced oxidative stress and neurotoxicity: implications for neurodegeneration in Alzheimer’s disease brain. A review.Free Radic Res 36: 1307–1313, 2002.PubMedGoogle Scholar
  94. 94.
    Floyd RA, Hensley K. Oxidative stress in brain aging. Implications for therapeutics of neurodegenerative diseases.Neurobiol Aging 23: 795–807, 2002.PubMedGoogle Scholar
  95. 95.
    Pratico D, Clark CM, Liun F, Lee VY-M, Trojanowski JQ. Increase of brain oxidative stress in mild cognitive impairment.Arch Neurol 59: 972–976, 2002.PubMedGoogle Scholar
  96. 96.
    Kourie JI. Mechanisms of amyloid β protein-induced modification of ion transport systems: implications of neurodegenerative diseases.Cell Mol Neurobiol 21: 173–213, 2001.PubMedGoogle Scholar
  97. 97.
    Beal MF. Mitochondria, free radicals, and neurodegeneration.Curr Opin Neurobiol 6: 661–666, 1996.PubMedGoogle Scholar
  98. 98.
    Bush AI. The metallobiology of Alzheimer’s disease.Trends Neurosci 26: 207–214, 2003.PubMedGoogle Scholar
  99. 99.
    Pratico D. Alzheimer’s disease and oxygen radicals: new insights.Biochem Pharmacol 63: 563–567, 2002.PubMedGoogle Scholar
  100. 100.
    Lim GP, Chu T, Yang F, Beech W, Frautschy SA, Cole GM. The curry spice curcumin reduces oxidative damage and amyloid pathology in an Alzheimer transgenic mouse.J Neurosci 21: 8370–8377, 2001.PubMedGoogle Scholar
  101. 101.
    Cole GM. Ironic fate: can a banned drug control metal heavies in neurodegenerative disease?Neuron 37: 889–893, 2003.PubMedGoogle Scholar
  102. 102.
    Cherny RA, Atwood CS, Xilinas ME, Gray DN, Jones WD, McLean CA et al. Treatment with a copper-zinc chelator markedly and rapidly inhibits β-amyloid accumulation in Alzheimer’s disease transgenic mice.Neuron 30: 665–676, 2001.PubMedGoogle Scholar
  103. 103.
    Morris MC, Evans DA, Bienias JL, Tangney CC, Bennett DA, Aggarwal N, Wilson RS, Scherr PA. Dietary intake of antioxidant nutrients and the risk of incident Alzheimer’s disease in a biracial community study.JAMA 287: 3230–3237, 2002.PubMedGoogle Scholar
  104. 104.
    Engelhart MJ, Geerlings MI, Ruitenberg A, van Swieten JC, Hofman A, Witteman JC, Breteler MM. Dietary intake of anti-oxidants and risk of Alzheimer’s disease.JAMA 287: 3223–3229, 2002.PubMedGoogle Scholar
  105. 105.
    Foley DJ, White LR. Dietary intake of antioxidants and risk of Alzheimer’s disease: food for thought.JAMA 287: 3261–3263, 2002.PubMedGoogle Scholar
  106. 106.
    Luchsinger JA, Tang M-X, Shea S, Mayeux R. Antioxidant vitamin intake and risk of Alzheimer’s disease.Arch Neurol 60: 203–208, 2003.PubMedGoogle Scholar
  107. 107.
    Sano M, Ernesto MS, Thomas RG, Klauber MR, Schafer K, Grundman M et al. A controlled trial of selegiline, alpha-tocopherol or both as a treatment for Alzheimer’s disease.N Engl J Med 336: 1216–1222, 1997.PubMedGoogle Scholar
  108. 108.
    Grundman M, Delaney P. Antioxidant strategies for Alzheimer’s disease.Proc Nutr Soc 61: 191–202, 2002.PubMedGoogle Scholar
  109. 109.
    Gutzmann H, Hadler D, Erzigkeit H. Long-term treatment of Alzheimer’s disease with idebenone. In: Alzheimer’s disease: biology, diagnosis and therapeutics (Iqbal K, Winbald B, Nishimura T, Takeda M, Wisniewski HM, eds), pp 687–705. UK: Wiley, 1997, 2002.Google Scholar
  110. 110.
    Choi DW. Calcium and excitotoxic neuronal injury.Ann NY Acad Sci 747: 162–171, 1994.PubMedGoogle Scholar
  111. 111.
    Butterfield DA, Pocernich C. The glutamatergic system in Alzheimer’s disease: therapeutic implications.CNS Drugs 17: 641–652, 2003.PubMedGoogle Scholar
  112. 112.
    Olney JW, Wozniak DF, Farber NB. Glutamate receptor dysfunction and Alzheimer’s disease.Restor Neurol Neurosci 13: 75–83, 1998.PubMedGoogle Scholar
  113. 113.
    Harris ME, Carney JM, Cole PS, Hensley K, Howard K, Howard BJ, Martin L et al. Beta-amyloid peptide-derived, oxygen-dependent free radicals inhibit glutamate uptake in cultured astrocytes: implications for Alzheimer’s disease.Neuroreport 6: 1875–1879, 1995.PubMedGoogle Scholar
  114. 114.
    Erdo SL, Schafer M. Memantine is highly potent in protecting cortical cultures against excitotoxic cell death evoked by glutamate andN-methyl-D-aspartate.Enr J Pharmacol 198: 215–217, 1991.Google Scholar
  115. 115.
    Parsons CG, Gruner J, Rozental J, Millar J, Lodge D. Patch clamp studies on the kinetics and selectivity of N-methyl-D-aspartate receptor antagonism by memantine (1-amino-3, 5-dimethyladamantan).Neuropharmacology 32: 1337–1350, 1993.PubMedGoogle Scholar
  116. 116.
    Miguel-Hidalgo JJ, Alvarez XA, Cacabelos R, Quack G. Neuroprotection by memantine against neurodegeneration induced by β-amyloid(l–40).Brain Res 958: 210–221, 2002.PubMedGoogle Scholar
  117. 117.
    Reisberg B, Doody R, Stoffler A, Schmitt F, Ferris S, Mobius HJ. Memantine in moderate-to-severe Alzheimer’s disease.N Engl J Med 348: 1333–1341, 2003.PubMedGoogle Scholar

Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc 2004

Authors and Affiliations

  1. 1.Department of NeurologyUniversity of North CarolinaChapel Hill
  2. 2.Department of NeurologyUniversity of CaliforniaSan Francisco
  3. 3.San Francisco VA Medical CenterSan Francisco

Personalised recommendations