Frontiers in Alzheimer's disease therapeutics

Therapeutic Advances in Chronic Disease

Volumn 2, Issue 1, 2011, Pages 9-23

  Stone, Jeremy G ^a   Casadesus, Gemma ^a   Gustaw Rothenberg, Kasia ^b   Siedlak, Sandra L ^a   Wang, Xinglong ^a   Zhu, Xiongwei ^a   Perry, George ^c   Castellani, Rudy J ^d   Smith, Mark A ^a  

^a CASE WESTERN RESERVE UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b INSTITUTE OF AGRICULTURAL MEDICINE   (Poland)

^c CASE WESTERN RESERVE UNIVERSITY   (United States)

^d UNIVERSITY OF MARYLAND SCHOOL OF MEDICINE   (United States)

Author keywords

Alzheimer's disease; amyloid; antioxidants; cholinesterase inhibitors; luteinizing hormone; mitochondrial therapy; neurodegenerative drugs; NMDA antagonists; tau

Indexed keywords

2 (2,4 DICHLOROPHENYL) 3 (1 METHYL 3 INDOLYL)MALEIMIDE; ALPHA TOCOPHEROL; ALZHEIMER DISEASE VACCINE; AMYLOID BETA PROTEIN; ANTIINFLAMMATORY AGENT; ASCORBIC ACID; BAPINEUZUMAB; DIMEBON; FOLIC ACID; LEUPRORELIN; LEVACECARNINE; LITHIUM CHLORIDE; LUTEINIZING HORMONE; MELATONIN; METHYLENE BLUE; MITOQ; NAPROXEN; NONSTEROID ANTIINFLAMMATORY AGENT; PHENSERINE; PHOSPHOTRANSFERASE INHIBITOR; PONEZUMAB; SEMAGACESTAT; SEROTONIN UPTAKE INHIBITOR; SOLANEZUMAB; TAU PROTEIN; THIAMET G; THIOCTIC ACID; UBIDECARENONE; UBIQUINONE DERIVATIVE; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ACTIVE IMMUNIZATION; ALZHEIMER DISEASE; ANTIOXIDANT ACTIVITY; BRAIN MITOCHONDRION; DEPRESSION; DIET SUPPLEMENTATION; DRUG MECHANISM; DRUG WITHDRAWAL; HUMAN; LIVER INJURY; MENINGOENCEPHALITIS; NERVOUS SYSTEM INFLAMMATION; NEUROFIBRILLARY TANGLE; NEUROPATHOLOGY; NONHUMAN; OXIDATIVE STRESS; PRIORITY JOURNAL; REVIEW; RISK REDUCTION; SYMPTOMATOLOGY;

EID: 79960068037     PISSN: 20406223     EISSN: 20406231     Source Type: Journal    
DOI: 10.1177/2040622310382817     Document Type: Review

References (160)

1. Aisen P.S. Davis K.L. Berg J.D. Schafer K. Campbell K. Thomas R.G. et al (2000) A randomized controlled trial of prednisone in Alzheimer's disease. Alzheimer's Disease Cooperative Study. Neurology 54: 588–593.
2. Aisen P.S. Schafer K.A. Grundman M. Pfeiffer E. Sano M. Davis K.L. et al (2003) Effects of rofecoxib or naproxen vs placebo on Alzheimer disease progression: a randomized controlled trial. JAMA 289: 2819–2826.
3. Aliev G. Liu J. Shenk J.C. Fischbach K. Pacheco G.J. Chen S.G. et al (2009) Neuronal mitochondrial amelioration by feeding acetyl-L-carnitine and lipoic acid to aged rats. J Cell Mol Med 13: 320–333.
4. Aliev G. Obrenovich M.E. Reddy V.P. Shenk J.C. Moreira P.I. Nunomura A. et al (2008) Antioxidant therapy in Alzheimer's disease: theory and practice. Mini Rev Med Chem 8: 1395–1406.
5. Aliev G. Smith M.A. Obrenovich M.E. de la Torre J.C. Perry G. (2003) Role of vascular hypoperfusion-induced oxidative stress and mitochondria failure in the pathogenesis of Azheimer disease. Neurotox Res 5: 491–504.
6. Ames B.N. Liu J. (2004) Delaying the mitochondrial decay of aging with acetylcarnitine. Ann N Y Acad Sci 1033: 108–116.
7. Ansari M.A. Scheff S.W. (2010) Oxidative stress in the progression of Alzheimer disease in the frontal cortex. J Neuropathol Exp Neurol 69: 155–167.
8. Apelt J. Schliebs R. (2001) Beta-amyloid-induced glial expression of both pro- and anti-inflammatory cytokines in cerebral cortex of aged transgenic Tg 2576 mice with Alzheimer plaque pathology. Brain Res 894: 21–30.
9. Arbus C. Gardette V. Bui E. Cantet C. Andrieu S. Nourhashemi F. et al (2010) Antidepressant use in Alzheimer's disease patients: results of the REAL.FR cohort. Int Psychogeriatr 22: 120–128.
10. Atwood C.S. Scarpa R.C. Huang X. Moir R.D. Jones W.D. Fairlie D.P. et al (2000) Characterization of copper interactions with alzheimer amyloid beta peptides: identification of an attomolar-affinity copper binding site on amyloid beta1-42. J Neurochem 75: 1219–1233.
11. Bachurin S.O. Shevtsova E.P. Kireeva E.G. Oxenkrug G.F. Sablin S.O. (2003) Mitochondria as a target for neurotoxins and neuroprotective agents. Ann N Y Acad Sci 993: 334–344, discussion 345–339.
12. Barten D.M. Guss V.L. Corsa J.A. Loo A. Hansel S.B. Zheng M. et al (2005) Dynamics of {beta}-amyloid reductions in brain, cerebrospinal fluid, and plasma of {beta}-amyloid precursor protein transgenic mice treated with a {gamma}-secretase inhibitor. J Pharmacol Exp Ther 312: 635–643.
13. Beal M.F. (2004) Mitochondrial dysfunction and oxidative damage in Alzheimer's and Parkinson's diseases and coenzyme Q 10 as a potential treatment. J Bioenerg Biomembr 36: 381–386.
14. Bonda D.J. Bajic V.P. Spremo-Potparevic B. Casadesus G. Zhu X. Smith M.A. et al (2010 a) Cell Cycle Aberrations and Neurodegeneration: A Review. Neuropathol Appl Neurobiol 36: 157–163.
15. Bonda D.J. Castellani R.J. Lee H.G. Tabaton M. Casadesus G. Perry G. et al (2010 b) Down syndrome and Alzheimer disease: a “multi-hit” hypothesis based on multiple contributing factors resulting in pleotrophic consequences. In: Ed. Urbano K.V. (ed.) Advances in Genetics Research, Vol. 2, Nova Science Publishers: Hauppauge, NY, 87–97.
16. Bonda D.J. Evans T.A. Santocanale C. Llosa J.C. Vina J. Bajic V.P. et al (2009) Evidence for the progression through S-phase in the ectopic cell cycle re-entry of neurons in Alzheimer disease. Aging (Albany NY) 1: 382–388.
17. Bowen R.L. Isley J.P. Atkinson R.L. (2000) An association of elevated serum gonadotropin concentrations and Alzheimer disease? J Neuroendocrinol 12: 351–354.
18. Bowen R.L. Smith M.A. Harris P.L. Kubat Z. Martins R.N. Castellani R.J. et al (2002) Elevated luteinizing hormone expression colocalizes with neurons vulnerable to Alzheimer's disease pathology. J Neurosci Res 70: 514–518.
19. Bowen R.L. Verdile G. Liu T. Parlow A.F. Perry G. Smith M.A. et al (2004) Luteinizing hormone, a reproductive regulator that modulates the processing of amyloid-beta precursor protein and amyloid-beta deposition. J Biol Chem 279: 20539–20545.
20. Brookmeyer R. Johnson E. Ziegler-Graham K. Arrighi H.M. (2007) Forecasting the global burden of Alzheimer's disease. Alzheimers Dement 3: 186–191.
21. Brunden K.R. Ballatore C. Crowe A. Smith A.B. III Lee V.M. Trojanowski J.Q. (2010) Tau-directed drug discovery for Alzheimer's disease and related tauopathies: a focus on tau assembly inhibitors. Exp Neurol 223: 304–310.
22. Brunden K.R. Trojanowski J.Q. Lee V.M. (2009) Advances in tau-focused drug discovery for Alzheimer's disease and related tauopathies. Nat Rev Drug Discov 8: 783–793.
23. Burns A. Whitehouse P. Arendt T. Forsti H. (1997) Alzheimer's disease in senile dementia: loss of neurones in the basal forebrain. Whitehouse, P., Price, D., Struble, R., Clarke, A., Coyle, J. and Delong, M. Science (1982), 215, 1237-1239. Int J Geriatr Psychiatry 12: 7–10.
24. Bush A.I. Pettingell W.H. Multhaup G. d Paradis M. Vonsattel J.P. Gusella J.F. et al (1994) Rapid induction of Alzheimer A beta amyloid formation by zinc. Science 265: 1464–1467.
25. Casadesus G. Webber K.M. Atwood C.S. Pappolla M.A. Perry G. Bowen R.L. et al (2006) Luteinizing hormone modulates cognition and amyloid-beta deposition in Alzheimer APP transgenic mice. Biochim Biophys Acta 1762: 447–452.
26. Castellani R.J. Harris P.L. Sayre L.M. Fujii J. Taniguchi N. Vitek M.P. et al (2001) Active glycation in neurofibrillary pathology of Alzheimer disease: N(epsilon)-(carboxymethyl) lysine and hexitol-lysine. Free Radic Biol Med 31: 175–180.
27. Castellani R.J. Lee H.G. Siedlak S.L. Nunomura A. Hayashi T. Nakamura M. et al (2009) Reexamining Alzheimer's disease: evidence for a protective role for amyloid-beta protein precursor and amyloid-beta. J Alzheimers Dis 18: 447–452.
28. Castellani R.J. Lee H.G. Zhu X. Nunomura A. Perry G. Smith M.A. (2006) Neuropathology of Alzheimer disease: pathognomonic but not pathogenic. Acta Neuropathol (Berl) 111: 503–509.
29. Castellani R.J. Nunomura A. Lee H.G. Perry G. Smith M.A. (2008) Phosphorylated tau: toxic, protective, or none of the above. J Alzheimers Dis 14: 377–383.
30. Chan D.C. (2006) Mitochondrial fusion and fission in mammals. Annu Rev Cell Dev Biol 22: 79–99.
31. Cole G.M. Frautschy S.A. (2010) Mechanisms of action of non-steroidal anti-inflammatory drugs for the prevention of Alzheimer's disease. CNS Neurol Disord Drug Targets 9: 140–148.
32. Cornelius C. Fastbom J. Winblad B. Viitanen M. (2004) Aspirin, NSAIDs, risk of dementia, and influence of the apolipoprotein E epsilon 4 allele in an elderly population. Neuroepidemiology 23: 135–143.
33. Corrada M.M. Kawas C.H. Hallfrisch J. Muller D. Brookmeyer R. (2005) Reduced risk of Alzheimer's disease with high folate intake: the Baltimore Longitudinal Study of Aging. Alzheimers Dement 1: 11–18.
34. Cotman C.W. Tenner A.J. Cummings B.J. (1996) beta-Amyloid converts an acute phase injury response to chronic injury responses. Neurobiol Aging 17: 723–731.
35. Crapper McLachlan D.R. Dalton A.J. Kruck T.P. Bell M.Y. Smith W.L. Kalow W. et al (1991) Intramuscular desferrioxamine in patients with Alzheimer's disease. Lancet 337: 1304–1308.
36. Crowe A. Huang W. Ballatore C. Johnson R.L. Hogan A.M. Huang R. et al (2009) Identification of aminothienopyridazine inhibitors of tau assembly by quantitative high-throughput screening. Biochemistry 48: 7732–7745.
37. Cuajungco M.P. Goldstein L.E. Nunomura A. Smith M.A. Lim J.T. Atwood C.S. et al (2000) Evidence that the beta-amyloid plaques of Alzheimer's disease represent the redox-silencing and entombment of abeta by zinc. J Biol Chem 275: 19439–19442.
38. Dickey C.A. Kamal A. Lundgren K. Klosak N. Bailey R.M. Dunmore J. et al (2007) The high-affinity HSP90-CHIP complex recognizes and selectively degrades phosphorylated tau client proteins. J Clin Invest 117: 648–658.
39. Doody R.S. Ferris S.H. Salloway S. Sun Y. Goldman R. Watkins W.E. et al (2009) Donepezil treatment of patients with MCI: a 48-week randomized, placebo-controlled trial. Neurology 72: 1555–1561.
40. Doody R.S. Gavrilova S.I. Sano M. Thomas R.G. Aisen P.S. Bachurin S.O. et al (2008) Effect of dimebon on cognition, activities of daily living, behaviour, and global function in patients with mild-to-moderate Alzheimer's disease: a randomised, double-blind, placebo-controlled study. Lancet 372: 207–215.
41. Engel T. Goni-Oliver P. Lucas J.J. Avila J. Hernandez F. (2006) Chronic lithium administration to FTDP-17 tau and GSK-3beta overexpressing mice prevents tau hyperphosphorylation and neurofibrillary tangle formation, but pre-formed neurofibrillary tangles do not revert. J Neurochem 99: 1445–1455.
42. Etminan M. Gill S. Samii A. (2003) Effect of non-steroidal anti-inflammatory drugs on risk of Alzheimer's disease: systematic review and meta-analysis of observational studies. BMJ 327: 128–129.
43. Exley C. (2006) Aluminium and iron, but neither copper nor zinc, are key to the precipitation of beta-sheets of Abeta_{42} in senile plaque cores in Alzheimer's disease. J Alzheimers Dis 10: 173–177.
44. Farlow M.R. Evans R.M. (1998) Pharmacologic treatment of cognition in Alzheimer's dementia. Neurology 51(1 Suppl 1): S36–S44, discussion S65–S37.
45. Fraser P.E. Nguyen J.T. Surewicz W.K. Kirschner D.A. (1991) pH-dependent structural transitions of Alzheimer amyloid peptides. Biophys J 60: 1190–1201.
46. Giacobini E. (2000) Cholinesterase inhibitors stabilize Alzheimer's disease. Ann N Y Acad Sci 920: 321–327.
47. Giacobini E. (2001) Do cholinesterase inhibitors have disease-modifying effects in Alzheimer's disease? CNS Drugs 15: 85–91.
48. Giacobini E. (2002) Long-term stabilizing effect of cholinesterase inhibitors in the therapy of Alzheimer' disease. J Neural Transm Suppl 62: 181–187.
49. Gillette Guyonnet S. Abellan van Kan G. Andrieu S. Barberger Gateau P. Berr C. Bonnefoy M. et al (2007) IANA task force on nutrition and cognitive decline with aging. J Nutr Health Aging 11: 132–152.
50. Griffin W.S. Sheng J.G. Roberts G.W. Mrak R.E. (1995) Interleukin-1 expression in different plaque types in Alzheimer's disease: significance in plaque evolution. J Neuropathol Exp Neurol 54: 276–281.
51. Hampel H. Ewers M. Burger K. Annas P. Mortberg A. Bogstedt A. et al (2009) Lithium trial in Alzheimer's disease: a randomized, single-blind, placebo-controlled, multicenter 10-week study. J Clin Psychiatry 70: 922–931.
52. Hayashi T. Shishido N. Nakayama K. Nunomura A. Smith M.A. Perry G. et al (2007) Lipid peroxidation and 4-hydroxy-2-nonenal formation by copper ion bound to amyloid-beta peptide. Free Radic Biol Med 43: 1552–1559.
53. Hernandez F. Borrell J. Guaza C. Avila J. Lucas J.J. (2002) Spatial learning deficit in transgenic mice that conditionally over-express GSK-3beta in the brain but do not form tau filaments. J Neurochem 83: 1529–1533.
54. Hirai K. Aliev G. Nunomura A. Fujioka H. Russell R.L. Atwood C.S. et al (2001) Mitochondrial abnormalities in Alzheimer's disease. J Neurosci 21: 3017–3023.
55. Honda K. Casadesus G. Petersen R.B. Perry G. Smith M.A. (2004) Oxidative stress and redox-active iron in Alzheimer's disease. Ann N Y Acad Sci 1012: 179–182.
56. Imahori K. Uchida T. (1997) Physiology and pathology of tau protein kinases in relation to Alzheimer's disease. J Biochem 121: 179–188.
57. in t' Veld B.A. Ruitenberg A. Hofman A. Launer L.J. van Duijn C.M. Stijnen T. et al (2001) Nonsteroidal antiinflammatory drugs and the risk of Alzheimer's disease. N Engl J Med 345: 1515–1521.
58. Jobling M.F. Huang X. Stewart L.R. Barnham K.J. Curtain C. Volitakis I. et al (2001) Copper and zinc binding modulates the aggregation and neurotoxic properties of the prion peptide PrP106-126. Biochemistry 40: 8073–8084.
59. Jorm A.F. Jolley D. (1998) The incidence of dementia: a meta-analysis. Neurology 51: 728–733.
60. Kalaria R.N. (1999) Microglia and Alzheimer's disease. Curr Opin Hematol 6: 15–24.
61. Kaminsky Y.G. Marlatt M.W. Smith M.A. Kosenko E.A. (2010) Subcellular and metabolic examination of amyloid-beta peptides in Alzheimer disease pathogenesis: evidence for Abeta(25-35). Exp Neurol 221: 26–37.
62. Kontush A. (2001) Alzheimer's amyloid-beta as a preventive antioxidant for brain lipoproteins. Cell Mol Neurobiol 21: 299–315.
63. Kontush A. Berndt C. Weber W. Akopyan V. Arlt S. Schippling S. et al (2001) Amyloid-beta is an antioxidant for lipoproteins in cerebrospinal fluid and plasma. Free Radic Biol Med 30: 119–128.
64. Kornhuber J. Bormann J. Retz W. Hubers M. Riederer P. (1989) Memantine displaces [3H]MK-801 at therapeutic concentrations in postmortem human frontal cortex. Eur J Pharmacol 166: 589–590.
65. Kwong L.K. Kamzalov S. Rebrin I. Bayne A.C. Jana C.K. Morris P. et al (2002) Effects of coenzyme Q (10) administration on its tissue concentrations, mitochondrial oxidant generation, and oxidative stress in the rat. Free Radic Biol Med 33: 627–638.
66. Larbig G. Pickhardt M. Lloyd D.G. Schmidt B. Mandelkow E. (2007) Screening for inhibitors of tau protein aggregation into Alzheimer paired helical filaments: a ligand based approach results in successful scaffold hopping. Curr Alzheimer Res 4: 315–323.
67. Lass A. Forster M.J. Sohal R.S. (1999) Effects of coenzyme Q 10 and alpha-tocopherol administration on their tissue levels in the mouse: elevation of mitochondrial alpha-tocopherol by coenzyme Q10. Free Radic Biol Med 26: 1375–1382.
68. Lee J. Boo J.H. Ryu H. (2009) The failure of mitochondria leads to neurodegeneration: Do mitochondria need a jump start? Adv Drug Deliv Rev 61: 1316–1323.
69. Lee Y.J. Jeong S.Y. Karbowski M. Smith C.L. Youle R.J. (2004) Roles of the mammalian mitochondrial fission and fusion mediators Fis1, Drp1, and Opa 1 in apoptosis. Mol Biol Cell 15: 5001–5011.
70. Lefebvre T. Ferreira S. Dupont-Wallois L. Bussiere T. Dupire M.J. Delacourte A. et al (2003) Evidence of a balance between phosphorylation and O-GlcNAc glycosylation of Tau proteins–a role in nuclear localization. Biochim Biophys Acta 1619: 167–176.
71. Lindsay J. Laurin D. Verreault R. Hebert R. Helliwell B. Hill G.B. et al (2002) Risk factors for Alzheimer's disease: a prospective analysis from the Canadian Study of Health and Aging. Am J Epidemiol 156: 445–453.
72. Liu F. Iqbal K. Grundke-Iqbal I. Hart G.W. Gong C.X. (2004) O-GlcNAcylation regulates phosphorylation of tau: a mechanism involved in Alzheimer's disease. Proc Natl Acad Sci U S A 101: 10804–10809.
73. Liu G. Men P. Harris P.L. Rolston R.K. Perry G. Smith M.A. (2006) Nanoparticle iron chelators: a new therapeutic approach in Alzheimer disease and other neurologic disorders associated with trace metal imbalance. Neurosci Lett 406: 189–193.
74. Liu G. Men P. Kudo W. Perry G. Smith M.A. (2009) Nanoparticle-chelator conjugates as inhibitors of amyloid-beta aggregation and neurotoxicity: a novel therapeutic approach for Alzheimer disease. Neurosci Lett 455: 187–190.
75. Liu J. Atamna H. Kuratsune H. Ames B.N. (2002 a) Delaying brain mitochondrial decay and aging with mitochondrial antioxidants and metabolites. Ann N Y Acad Sci 959: 133–166.
76. Liu J. Head E. Gharib A.M. Yuan W. Ingersoll R.T. Hagen T.M. et al (2002 b) Memory loss in old rats is associated with brain mitochondrial decay and RNA / DNA oxidation: partial reversal by feeding acetyl-L-carnitine and / or R-alpha -lipoic acid. Proc Natl Acad Sci U S A 99: 2356–2361.
77. Liu J. Killilea D.W. Ames B.N. (2002 c) Age-associated mitochondrial oxidative decay: improvement of carnitine acetyltransferase substrate-binding affinity and activity in brain by feeding old rats acetyl-L- carnitine and / or R-alpha -lipoic acid. Proc Natl Acad Sci U S A 99: 1876–1881.
78. Liu Q. Xie F. Rolston R. Moreira P.I. Nunomura A. Zhu X. et al (2007) Prevention and treatment of Alzheimer disease and aging: antioxidants. Mini Rev Med Chem 7: 171–180.
79. Long J. Gao F. Tong L. Cotman C.W. Ames B.N. Liu J. (2009) Mitochondrial decay in the brains of old rats: ameliorating effect of alpha-lipoic acid and acetyl-L-carnitine. Neurochem Res 34: 755–763.
80. Lu C. Zhang D. Whiteman M. Armstrong J.S. (2008) Is antioxidant potential of the mitochondrial targeted ubiquinone derivative MitoQ conserved in cells lacking mtDNA? Antioxid Redox Signal 10: 651–660.
81. Lucas J.J. Hernandez F. Gomez-Ramos P. Moran M.A. Hen R. Avila J. (2001) Decreased nuclear beta-catenin, tau hyperphosphorylation and neurodegeneration in GSK-3beta conditional transgenic mice. EMBO J 20: 27–39.
82. Lundkvist J. Naslund J. (2007) Gamma-secretase: a complex target for Alzheimer's disease. Curr Opin Pharmacol 7: 112–118.
83. Luo W. Dou F. Rodina A. Chip S. Kim J. Zhao Q. et al (2007) Roles of heat-shock protein 90 in maintaining and facilitating the neurodegenerative phenotype in tauopathies. Proc Natl Acad Sci U S A 104: 9511–9516.
84. Mackenzie I.R. Hao C. Munoz D.G. (1995) Role of microglia in senile plaque formation. Neurobiol Aging 16: 797–804.
85. Mancuso M. Orsucci D. Siciliano G. Murri L. (2008) Mitochondria, mitochondrial DNA and Alzheimer's disease. What comes first? Curr Alzheimer Res 5: 457–468.
86. Marlatt M.W. Webber K.M. Moreira P.I. Lee H.G. Casadesus G. Honda K. et al (2005) Therapeutic opportunities in Alzheimer disease: one for all or all for one? Curr Med Chem 12: 1137–1147.
87. Masters C.L. Simms G. Weinman N.A. Multhaup G. McDonald B.L. Beyreuther K. (1985) Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci U S A 82: 4245–4249.
88. McGeer P.L. Schulzer M. McGeer E.G. (1996) Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer's disease: a review of 17 epidemiologic studies. Neurology 47: 425–432.
89. McShane R. Areosa Sastre A. Minakaran N. (2006) Memantine for dementia. Cochrane Database Syst Rev 2: CD003154–CD003154.
90. Middleton L.E. Yaffe K. (2009) Promising strategies for the prevention of dementia. Arch Neurol 66: 1210–1215.
91. Milgram N.W. Araujo J.A. Hagen T.M. Treadwell B.V. Ames B.N. (2007) Acetyl-L-carnitine and alpha-lipoic acid supplementation of aged beagle dogs improves learning in two landmark discrimination tests. FASEB J 21: 3756–3762.
92. Moore A.H. O'Banion M.K. (2002) Neuroinflammation and anti-inflammatory therapy for Alzheimer's disease. Adv Drug Deliv Rev 54: 1627–1656.
93. Moreira P.I. Zhu X. Nunomura A. Smith M.A. Perry G. (2006) Therapeutic options in Alzheimer's disease. Expert Rev Neurother 6: 897–910.
94. Murphy M.P. (2001) Development of lipophilic cations as therapies for disorders due to mitochondrial dysfunction. Expert Opin Biol Ther 1: 753–764.
95. Murphy M.P. Smith R.A. (2007) Targeting antioxidants to mitochondria by conjugation to lipophilic cations. Annu Rev Pharmacol Toxicol 47: 629–656.
96. Nakamura M. Shishido N. Nunomura A. Smith M.A. Perry G. Hayashi Y. et al (2007) Three histidine residues of amyloid-beta peptide control the redox activity of copper and iron. Biochemistry 46: 12737–12743.
97. Neugroschl J. Sano M. (2009) An update on treatment and prevention strategies for Alzheimer's disease. Curr Neurol Neurosci Rep 9: 368–376.
98. Noble W. Planel E. Zehr C. Olm V. Meyerson J. Suleman F. et al (2005) Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degeneration in vivo. Proc Natl Acad Sci U S A 102: 6990–6995.
99. Nunomura A. Castellani R.J. Lee H.G. Moreira P.I. Zhu X. Perry G. et al (2006) Neuropathology in Alzheimer's disease: awaking from a hundred-year-old dream. Sci Aging Knowledge Environ 8: pe10–pe10.
100. Nunomura A. Tamaoki T. Tanaka K. Motohashi N. Nakamura M. Hayashi T. et al (2010) Intraneuronal amyloid beta accumulation and oxidative damage to nucleic acids in Alzheimer disease. Neurobiol Dis 37: 731–737.
101. Ogawa O. Zhu X. Perry G. Smith M.A. (2002) Mitochondrial abnormalities and oxidative imbalance in neurodegenerative disease. Sci Aging Knowledge Environ 41: pe16–pe16.
102. Okada H. Doken Y. Ogawa Y. (1996) Persistent suppression of the pituitary-gonadal system in female rats by three-month depot injectable microspheres of leuprorelin acetate. J Pharm Sci 85: 1044–1048.
103. Olcese J.M. Cao C. Mori T. Mamcarz M.B. Maxwell A. Runfeldt M.J. et al (2009) Protection against cognitive deficits and markers of neurodegeneration by long-term oral administration of melatonin in a transgenic model of Alzheimer disease. J Pineal Res 47: 82–96.
104. Opazo C. Huang X. Cherny R.A. Moir R.D. Roher A.E. White A.R. et al (2002) Metalloenzyme-like activity of Alzheimer's disease beta-amyloid. Cu-dependent catalytic conversion of dopamine, cholesterol, and biological reducing agents to neurotoxic H (2)O (2). J Biol Chem 277: 40302–40308.
105. Pappolla M. Bozner P. Soto C. Shao H. Robakis N.K. Zagorski M. et al (1998) Inhibition of Alzheimer beta-fibrillogenesis by melatonin. J Biol Chem 273: 7185–7188.
106. Parks J.K. Smith T.S. Trimmer P.A. Bennett J.P. Jr Parker W.D. Jr (2001) Neurotoxic Abeta peptides increase oxidative stress in vivo through NMDA-receptor and nitric-oxide-synthase mechanisms, and inhibit complex IV activity and induce a mitochondrial permeability transition in vitro. J Neurochem 76: 1050–1056.
107. Perez M. Hernandez F. Lim F. Diaz-Nido J. Avila J. (2003) Chronic lithium treatment decreases mutant tau protein aggregation in a transgenic mouse model. J Alzheimers Dis 5: 301–308.
108. Perrig W.J. Perrig P. Stahelin H.B. (1997) The relation between antioxidants and memory performance in the old and very old. J Am Geriatr Soc 45: 718–724.
109. Perry G. Nunomura A. Raina A.K. Smith M.A. (2000) Amyloid-beta junkies. Lancet 355: 757–758.
110. Perry G. Rizzuto N. Autilio-Gambetti L. Gambetti P. (1985) Paired helical filaments from Alzheimer disease patients contain cytoskeletal components. Proc Natl Acad Sci U S A 82: 3916–3920.
111. Petersen R.B. Nunomura A. Lee H.G. Casadesus G. Perry G. Smith M.A. et al (2007) Signal transduction cascades associated with oxidative stress in Alzheimer's disease. J Alzheimers Dis 11: 143–152.
112. Piani D. Spranger M. Frei K. Schaffner A. Fontana A. (1992) Macrophage-induced cytotoxicity of N-methyl-D-aspartate receptor positive neurons involves excitatory amino acids rather than reactive oxygen intermediates and cytokines. Eur J Immunol 22: 2429–2436.
113. Pickhardt M. Gazova Z. von Bergen M. Khlistunova I. Wang Y. Hascher A. et al (2005) Anthraquinones inhibit tau aggregation and dissolve Alzheimer's paired helical filaments in vitro and in cells. J Biol Chem 280: 3628–3635.
114. Poeggeler B. Miravalle L. Zagorski M.G. Wisniewski T. Chyan Y.J. Zhang Y. et al (2001) Melatonin reverses the profibrillogenic activity of apolipoprotein E 4 on the Alzheimer amyloid Abeta peptide. Biochemistry 40: 14995–15001.
115. Qiu C. de Ronchi D. Fratiglioni L. (2007) The epidemiology of the dementias: an update. Curr Opin Psychiatry 20: 380–385.
116. Regland B. Lehmann W. Abedini I. Blennow K. Jonsson M. Karlsson I. et al (2001) Treatment of Alzheimer's disease with clioquinol. Dement Geriatr Cogn Disord 12: 408–414.
117. Reines S.A. Block G.A. Morris J.C. Liu G. Nessly M.L. Lines C.R. et al (2004) Rofecoxib: no effect on Alzheimer's disease in a 1-year, randomized, blinded, controlled study. Neurology 62: 66–71.
118. Relkin N.R. Szabo P. Adamiak B. Burgut T. Mon the C. Lent R.W. et al (2009) 18-Month study of intravenous immunoglobulin for treatment of mild Alzheimer disease. Neurobiol Aging 30: 1728–1736.
119. Ritchie C.W. Bush A.I. Mackinnon A. Macfarlane S. Mastwyk M. MacGregor L. et al (2003) Metal-protein attenuation with iodochlorhydroxyquin (clioquinol) targeting Abeta amyloid deposition and toxicity in Alzheimer disease: a pilot phase 2 clinical trial. Arch Neurol 60: 1685–1691.
120. Rogers J. Kirby L.C. Hempelman S.R. Berry D.L. McGeer P.L. Kaszniak A.W. et al (1993) Clinical trial of indomethacin in Alzheimer's disease. Neurology 43: 1609–1611.
121. Rosenberg P.B. Drye L.T. Martin B.K. Frangakis C. Mintzer J.E. Weintraub D. et al (2010) Sertraline for the treatment of depression in Alzheimer disease. Am J Geriatr Psychiatry 18: 136–145.
122. Rottkamp C.A. Raina A.K. Zhu X. Gaier E. Bush A.I. Atwood C.S. et al (2001) Redox-active iron mediates amyloid-beta toxicity. Free Radic Biol Med 30: 447–450.
123. Sabbagh M.N. (2009) Drug development for Alzheimer's disease: where are we now and where are we headed? Am J Geriatr Pharmacother 7: 167–185.
124. Sano M. Ernesto C. Thomas R.G. Klauber M.R. Schafer K. Grundman M. et al (1997) A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's disease. The Alzheimer's Disease Cooperative Study. N Engl J Med 336: 1216–1222.
125. Sasaki A. Yamaguchi H. Ogawa A. Sugihara S. Nakazato Y. (1997) Microglial activation in early stages of amyloid beta protein deposition. Acta Neuropathol 94: 316–322.
126. Scharf S. Mander A. Ugoni A. Vajda F. Christophidis N. (1999) A double-blind, placebo-controlled trial of diclofenac / misoprostol in Alzheimer's disease. Neurology 53 (1): 197–201.
127. Schubert D. Chevion M. (1995) The role of iron in beta amyloid toxicity. Biochem Biophys Res Commun 216: 702–707.
128. Selenica M.L. Jensen H.S. Larsen A.K. Pedersen M.L. Helboe L. Leist M. et al (2007) Efficacy of small-molecule glycogen synthase kinase-3 inhibitors in the postnatal rat model of tau hyperphosphorylation. Br J Pharmacol 152: 959–979.
129. Shah R.S. Lee H.G. Xiongwei Z. Perry G. Smith M.A. Castellani R.J. (2008) Current approaches in the treatment of Alzheimer's disease. Biomed Pharmacother 62: 199–207.
130. Shiurba R.A. Ishiguro K. Takahashi M. Sato K. Spooner E.T. Mercken M. et al (1996) Immunocytochemistry of tau phosphoserine 413 and tau protein kinase I in Alzheimer pathology. Brain Res 737: 119–132.
131. Short R.A. Bowen R.L. O'Brien P.C. Graff-Radford N.R. (2001) Elevated gonadotropin levels in patients with Alzheimer disease. Mayo Clin Proc 76: 906–909.
132. Siddique H. Hynan L.S. Weiner M.F. (2009) Effect of a serotonin reuptake inhibitor on irritability, apathy, and psychotic symptoms in patients with Alzheimer's disease. J Clin Psychiatry 70: 915–918.
133. Siedlak S.L. Casadesus G. Webber K.M. Pappolla M.A. Atwood C.S. Smith M.A. et al (2009) Chronic antioxidant therapy reduces oxidative stress in a mouse model of Alzheimer's disease. Free Radic Res 43: 156–164.
134. Smith M.A. (1998) Alzheimer disease. Int Rev Neurobiol 42: 1–54.
135. Smith M.A. Atwood C.S. Joseph J.A. Perry G. (2002) Predicting the failure of amyloid-beta vaccine. Lancet 359: 1864–1865.
136. Smith M.A. Nunomura A. Zhu X. Takeda A. Perry G. (2000) Metabolic, metallic, and mitotic sources of oxidative stress in Alzheimer disease. Antioxid Redox Signal 2: 413–420.
137. Smith M.A. Zhu X. Tabaton M. Liu G. McKeel D.W. Jr Cohen M.L. et al (2010 a) Increased iron and free radical generation in preclinical Alzheimer disease and mild cognitive impairment. J Alzheimers Dis 19: 363–372.
138. Smith M.A. Zhu X. Tabaton M. Liu G. McKeel D.W. Jr Cohen M.L. et al (2010 b) Increased iron and free radical generation in preclinical alzheimer disease and mild cognitive impairment. J Alzheimers Dis 19: 363–372.
139. Smith R.A. Kelso G.F. James A.M. Murphy M.P. (2004) Targeting coenzyme Q derivatives to mitochondria. Methods Enzymol 382: 45–67.
140. Stewart W.F. Kawas C. Corrada M. Metter E.J. (1997) Risk of Alzheimer's disease and duration of NSAID use. Neurology 48: 626–632.
141. Su B. Wang X. Zheng L. Perry G. Smith M.A. Zhu X. (2010) Abnormal mitochondrial dynamics and neurodegenerative diseases. Biochim Biophys Acta 1802: 135–142.
142. Tan U. Kutlu N. (1991) The distribution of paw preference in right-, left-, and mixed pawed male and female cats: the role of a female right-shift factor in handedness. Int J Neurosci 59: 219–229.
143. van Dyck C.H. Tariot P.N. Meyers B. Malca Resnick E. (2007) A 24-week randomized, controlled trial of memantine in patients with moderate-to-severe Alzheimer disease. Alzheimer Dis Assoc Disord 21: 136–143.
144. van Gool W.A. Weinstein H.C. Scheltens P. Walstra G.J. (2001) Effect of hydroxychloroquine on progression of dementia in early Alzheimer's disease: an 18-month randomised, double-blind, placebo-controlled study. Lancet 358: 455–460.
145. Wadsworth T.L. Bishop J.A. Pappu A.S. Woltjer R.L. Quinn J.F. (2008) Evaluation of coenzyme Q as an antioxidant strategy for Alzheimer's disease. J Alzheimers Dis 14: 225–234.
146. Wang X. Su B. Fujioka H. Zhu X. (2008 a) Dynamin-like protein 1 reduction underlies mitochondrial morphology and distribution abnormalities in fibroblasts from sporadic Alzheimer's disease patients. Am J Pathol 173: 470–482.
147. Wang X. Su B. Siedlak S.L. Moreira P.I. Fujioka H. Wang Y. et al (2008 b) Amyloid-beta overproduction causes abnormal mitochondrial dynamics via differential modulation of mitochondrial fission / fusion proteins. Proc Natl Acad Sci U S A 105: 19318–19323.
148. Wang X. Su B. Zheng L. Perry G. Smith M.A. Zhu X. (2009) The role of abnormal mitochondrial dynamics in the pathogenesis of Alzheimer's disease. J Neurochem 109(Suppl. 1): 153–159.
149. Webber K.M. Casadesus G. Bowen R.L. Perry G. Smith M.A. (2007 a) Evidence for the role of luteinizing hormone in Alzheimer disease. Endocr Metab Immune Disord Drug Targets 7: 300–303.
150. Webber K.M. Perry G. Smith M.A. Casadesus G. (2007 b) The contribution of luteinizing hormone to Alzheimer disease pathogenesis. Clin Med Res 5: 177–183.
151. Wegiel J. Wang K.C. Imaki H. Rubenstein R. Wronska A. Osuchowski M. et al (2001) The role of microglial cells and astrocytes in fibrillar plaque evolution in transgenic APP(SW) mice. Neurobiol Aging 22: 49–61.
152. Whitehouse P.J. (2006) Quality of life: the bridge from the cholinergic basal forebrain to cognitive science and bioethics. J Alzheimers Dis 9(3 Suppl): 447–453.
153. Wong G.T. Manfra D. Poulet F.M. Zhang Q. Josien H. Bara T. et al (2004) Chronic treatment with the gamma-secretase inhibitor LY-411,575 inhibits beta-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation. J Biol Chem 279: 12876–12882.
154. Zandi P.P. Anthony J.C. Khachaturian A.S. Stone S.V. Gustafson D. Tschanz J.T. et al (2004) Reduced risk of Alzheimer disease in users of antioxidant vitamin supplements: the Cache County Study. Arch Neurol 61: 82–88.
155. Zhang H. Burrows F. (2004) Targeting multiple signal transduction pathways through inhibition of Hsp90. J Mol Med 82: 488–499.
156. Zhu X. Castellani R.J. Takeda A. Nunomura A. Atwood C.S. Perry G. et al (2001) Differential activation of neuronal ERK, JNK / SAPK and p 38 in Alzheimer disease: the ‘two hit’ hypothesis. Mech Ageing Dev 123: 39–46.
157. Zhu X. Lee H.G. Perry G. Smith M.A. (2007) Alzheimer disease, the two-hit hypothesis: an update. Biochim Biophys Acta 1772: 494–502.
158. Zhu X. Perry G. Moreira P.I. Aliev G. Cash A.D. Hirai K. et al (2006) Mitochondrial abnormalities and oxidative imbalance in Alzheimer disease. J Alzheimers Dis 9: 147–153.
159. Zhu X. Raina A.K. Perry G. Smith M.A. (2004) Alzheimer's disease: the two-hit hypothesis. Lancet Neurol 3: 219–226.
160. Ziegler-Graham K. Brookmeyer R. Johnson E. Arrighi H.M. (2008) Worldwide variation in the doubling time of Alzheimer's disease incidence rates. Alzheimers Dement 4: 316–323.