Current experimental therapy for Alzheimer's disease

Current Neuropharmacology

Volumn 5, Issue 2, 2007, Pages 127-134

  Chen, Sheng ^a   Zhang, Xiao Jie ^b   Li, Liang ^b   Le, Wei Dong ^a,b  

^a SHANGHAI JIAO TONG UNIVERSITY SCHOOL OF MEDICINE   (China)

^b SHANGHAI UNIVERSITY OF MEDICINE AND HEALTH SCIENCES   (China)

Author keywords

Alzheimer's disease; Amyloid plaque; Experimental approach; Gene therapy; Immunotherapy; Neurofibrillary tangles; Secretase; Small interfering molecule

Indexed keywords

ADENOSINE RECEPTOR BLOCKING AGENT; ALPHA SECRETASE; ALZHEIMER DISEASE VACCINE; AMYLOID A PROTEIN; AMYLOID BETA PROTEIN; AMYLOID PRECURSOR PROTEIN; ANTIINFLAMMATORY AGENT; ANTIOXIDANT; BENZENESULFONAMIDE; BENZOLACTAM; BETA SECRETASE INHIBITOR; BMS 289948; BMS 299897; BRYOSTATIN 1; ENOXAPARIN; FLUOROBENZENEPROPANOIC ACID; GAMMA SECRETASE INHIBITOR; INSULINASE; L 685458; L 852646; LENTIVIRUS VECTOR; LOW MOLECULAR WEIGHT HEPARIN; LY 450139; MEMBRANE METALLOENDOPEPTIDASE; MONOCLONAL ANTIBODY; MONOCLONAL ANTIBODY M266; NICASTRIN; PLACEBO; PROTEIN KINASE C ACTIVATOR; SMALL INTERFERING RNA; UNCLASSIFIED DRUG; UNINDEXED DRUG; WO 9822494;

ALZHEIMER DISEASE; ANTIINFLAMMATORY ACTIVITY; ANTIOXIDANT ACTIVITY; APOPTOSIS; BLOOD BRAIN BARRIER; CLINICAL TRIAL; DRUG MECHANISM; DRUG SAFETY; DRUG TARGETING; DRUG TOLERABILITY; ENCEPHALITIS; ENZYME ACTIVATION; HORMONE SUBSTITUTION; HUMAN; IMMUNOTHERAPY; NEURAL STEM CELL TRANSPLANTATION; NEUROFIBRILLARY TANGLE; NEUROPROTECTION; NONHUMAN; PROTEIN DEGRADATION; PROTEIN EXPRESSION; PROTEIN PROCESSING; PROTEIN TARGETING; REVIEW; VIRAL GENE DELIVERY SYSTEM; VIRAL GENE THERAPY;

EID: 34347372183     PISSN: 1570159X     EISSN: None     Source Type: Journal    
DOI: 10.2174/157015907780866901     Document Type: Review

References (96)

1. Adessi, C., Frossard, M.J., Boissard, C., Fraga, S., Bieler, S., Ruckle, T., Vilbois, F., Robinson, S.M., Mutter, M., Banks, W.A., Soto, C. (2003) Pharmacological profiles of peptide drug candidates for the treatment of Alzheimer's disease. J. Biol. Chem., 278, 13905-11.
2. Adlard, P.A., Perreau, V.M., Pop, V., Cotman, C.W. (2005) Voluntary exercise decreases amyloid load in a transgenic model of Alzheimer's disease. J. Neurosci., 25, 4217-21.
3. Agdeppa, E.D., Kepe, V., Liu, J. (2003) 2-Dialkylamino-6- acylmalononitrile substituted naphthalenes (DDNP analogs): novel diagnostic and therapeutic tools in Alzheimer's disease. Mol. Imaging Biol., 5, 404-17.
4. Alkon, D.L., Epstein, H., Kuzirian, A., Bennett, M.C, Nelson, T.J. (2005) Protein synthesis required for long-term memory is induced by PKC activation on days before associative learning. Proc. Natl. Acad. Sci. USA, 102, 16432-7.
5. Anderson, J.J., Holtz, G., Baskin, P.P. (2005) Reductions in beta-amyloid concentrations in vivo by the gamma-secretase inhibitors BMS-289948 and BMS-299897. Biochem. Pharmacol., 69, 689-98.
6. Appel, S.H., Smith, R.G., Le, W.D. (1996) Immune-mediated cell death in neurodegenerative disease. Adv. Neurol., 69, 153-9.
7. Arbel, M., Yacoby, I., Solomon, B. (2005) Inhibition of amyloid precursor protein processing by β-secretase through site-directed antibodies. Proc. Natl. Acad. Sci. USA, 102, 7718-23.
8. Arenas, E. (1996) GDNF, a multispecific neurotrophic factor with potential therapeutic applications in neurodegenerative disorders. Mol. Psychiatry, 1, 179-82.
9. Bard, F., Cannon, C., Barbour, R., Burke, R.L., Games, D., Grajeda, H., Guido, T., Hu, K., Huang, J., Johnson-Wood, K. (2000) Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat. Med., 6, 916-919.
10. Barten, D.M., Guss, V.L., Corsal, J.A., Loo, A., Hansel, S.B., Zheng, M. (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. Pharmacol. Exp. Ther., 312, 635-43.
11. Bergamaschini, L., Rossi, E., Storini, C., Pizzimenti, S., Distaso, M., Perego, C. (2004) Peripheral treatment with enoxaparin, a low molecular weight heparin, reduces plaques and beta-amyloid accumulation in a mouse model of Alzheimer's disease. J. Neurosci., 24, 4181-4186.
12. Bhat, R., Xue, Y., Berg, S., Hellberg, S., Ormo, M., Nilsson, Y., Radesater, A.C., Jerning, E. (2003) Structural insights and biological effects of glycogen synthase kinase 3-specific inhibitor AR-A014418. Biol. Chem., 278, 45937-45.
13. Blesch, A., Tuszynski, M.H. (2004) Gene therapy and cell transplantation for Alzheimer's disease and spinal cord injury. Yonsei. Med. J., 45, 28-31.
14. Boche, D., Nicoll, J.A., Weller, R.O. (2005) Immunotherapy for Alzheimer's disease and other dementias. Curr. Opin. Neurol., 18, 720-5.
15. Braddock, M. (2005) Safely slowing down the decline in Alzheimer's disease: gene therapy shows potential. Expert Opin. Investig. Drugs, 14, 913-5.
16. Bubber, P., Haroutunian, V., Fisch, G., Blass, J.P., Gibson, G.E. (2005) Mitochondrial abnormalities in Alzheimer brain: mechanistic implications. Ann. Neurol., 57, 695-703.
17. Cataldo, A.M., Peterhoff, C.M., Schmidt, S.D., Terio, N.B., Duff, K., Beard, M., Mathews, P.M., Nixon, R.A. (2004) Presenilin mutations in familial Alzheimer disease and transgenic mouse models accelerate neuronal lysosomal pathology. J. Neuropathol. Exp. Neurol., 63, 821-30.
18. Chacon, M.A., Barria, M.I., Soto, C., Inestrosa, N.C. (2004) Beta-sheet breaker peptide prevents Abeta-induced spatial memory impairments with partial reduction of amyloid deposits. Mol. Psychiatry, 9, 953-61.
19. Chang, W.P., Koelsch, G., Wong, S., Downs, D., Da, H., Weerasena, V., Gordon, B., Devasamudram, T., Bilcer, G., Ghosh, A.K., Tang, J. (2004) In vivo inhibition of Abeta production by memapsin 2 (beta-secretase) inhibitors. J. NeuroChem., 89, 1409-16.
20. Clark, C.M., Karlawish, J.H. (2003) Alzheimer disease: Current concepts and emerging diagnostic and therapeutic strategies. Ann. Intern. Med., 138, 400-410.
21. Cruts, M., Rademakers, R., Gijselinck, I., van der Zee, J., Dermaut, B., de Pooter, T., de Rijk, P., Del-Favero, J., van Broeckhoven, C. (2005) Genomic architecture of human 17q21 linked to frontotemporal dementia uncovers a highly homologous family of low-copy repeats in the tau region. Hum. Mol. Genet., 14, 1753-62.
22. Dall'Igna, O.P., Porciuncula, L.O., Souza, D.O., Cunha, R.A., Lara, D.R. (2003) Neuroprotection by caffeine and adenosine A2A receptor blockade of beta-amyloid neurotoxicity. Br. J. Pharmacol., 138, 1207-9.
23. DeMattos, R.B., Bales, K.R., Cummins, D.J., Dodart, J.C., Paul, S.M., Holtzman, D.M. (2000) Peripheral anti-A beta antibody alters CNS and plasma A beta clearance and decreases brain A beta burden in a mouse model of Alzheimer's disease. Proc. Natl. Acad. Sci. USA, 98, 8850-8855.
24. Dodart, J.C., Marr, R.A., Koistinaho, M., Gregersen, B.M., Malkani, S., Verma, I.M., Paul, S.M. (2005) Gene delivery of human apolipoprotein E alters brain Aβburden in a mouse model of Alzheimer's disease. Proc. Natl. Acad. Sci. USA, 102, 1211-1216.
25. Dodel, R.C., Du, Y., Depboylu, C., Hampel, H., Froich, L., Haag, A., Hemmeter, U., Paulsen, S., Teipel, S.J., Brettschneider, S., Moler, H.J., Wei, X., Farlow, M., Sommer, N., Oertel, W.H. (2004) Intravenous immunoglobulins containing antibodies against b-amyloid for the treatment of Alzheimer's disease. J. Neurol. Neurosurg. Psychiatry, 75, 1472-4.
26. Engelhardt, J.I., Le, W.D., Siklos, L., Obal, I., Boda, K., Appel, S.H. (2000) Stereotaxic injection of IgG from patients with Alzheimer disease initiates injury of cholinergic neurons of the basal forebrain. Arch. Neurol., 57, 681-6.
27. Eriksen, J.L., Sagi, S.A., Smith, T.E., Weggen, S., Das, P. (2003) NSAIDs and enantiomers of flurbiprofen target γ-secretase and lower Aβ42 in vivo. J. Clin. Invest., 112, 440-449.
28. Etcheberrigaray, R., Tan, M., Dewachter, I., Kuiperi, C. (2004) Therapeutic effects of PKC activators in Alzheimer's disease transgenic mice. Proc. Natl. Acad. Sci. USA, 101, 11141-11146.
29. Fahrenholz, F., Postina, R. (2006) α-secretase activation- An approach to Alzheimer's disease therapy. Neurodegener. Dis., 3, 255-261.
30. Feldman, H., Gauthier, S., Hecker, J., Vellas, B., Subbiah, P., Whalen, E., the Donepezil MSAD Study Investigators Group. (2001) A 24-week, randomized, double-blind study of donepezil in moderate to severe Alzheimer's disease. Neurology, 57, 613-20.
31. Frenkel, D., Maron, R., Burt, D.S., Weiner, H.L. (2005) Nasal vaccination with a proteosome-based adjuvant and glatiramer acetate clears beta-amyloid in a mouse model of Alzheimer disease. J. Clin. Invest., 115, 2423-2433.
32. Gelinas, D.S., Salilva, K., Fenili, D., George-Hyslop, P., Mclaurin, J. (2004) Immunotherapy for Alzheimer's disease. Proc. Natl. Acad. Sci. USA, 101, 14657-14662.
33. Geling, A., Steiner, H., Willem, M., Bally-Cuif, L., Haass, C. (2002) A gamma-secretase inhibitor blocks Notch signaling in vivo and causes a severe neurogenic phenotype in zebrafish. EMBO Rep., 3, 688-94.
34. Ghochikyan, A., Vasilevko, V., Petrushina, I., Movsesyan, N., Babikyan, D. (2003) Generation and characterization of the humoral immune response to DNA immunization with a chimeric beta-amyloid-interleukin-4 minigene. Eur. J. Immunol., 33, 3232-41.
35. Ghosh, A.K., Shin, D., Downs, D., Koelsch, G., Lin, X., Ermolieff, J., Tang, J. (2001) Design of potent inhibitors for human brain Memapsin 2 (β-secretase). J. Am. Chem. Soc., 122, 3522-3523.
36. Gruninger-Leitch, F., Schlatter, D., Kung, E., Nelbock, P., Dobeli, H. (2002) Substrate and inhibitor profile of β-secretase (beta-secretase) and comparison with other mammalian aspartic proteases. J. Biol. Chem., 277, 4687-93.
37. Hock, C., Konietzko, U., Streffer, J.R., Tracy, J., Signorell, A. (2003) Antibodies against beta-amyloid slow cognitive decline in Alzheimer's disease. Neuron, 38, 547-54.
38. Hong, L., Koelsch, G., Lin, X., Wu, S., Terzyan, S., Ghosh, A.K., Zhang, X.C., Tang, J. (2000) Structure of the protease domain of memapsin 2 (β-secretase) complexed with inhibitor. Science (Wash DC), 290, 150-153.
39. Hughes, I.A. (2004) A perspective on stem cells by a clinician. Eur. J. Endocrinol., 151(Suppl. 3), U3-5.
40. Kalman, J., Engelhardt, J.I., Le, W.D., Xie, W., Kovacs, I., Kasa, P., Appel, S.H. (1997) Experimental immune-mediated damage of septal cholinergic neurons. J. Neuroimmunol., 77, 63-74.
41. Kao, S.C., Krichevsky, A.M., Kosik, K.S., Tsai, L.H. (2004) β-secretase1 suppression by RNA interference in primary cortical neurons. Biol. Chem., 279, 1942-1949.
42. Klunk, W.E., Engler, H., Nordberg, A., Wang, Y., Blomqvist, G., Holt, D.P. (2004) Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound-B. Ann. Neurol., 55, 306-19.
43. Kurreck, J. (2003) Antisense technologies, improvement through novel chemical modifications. Eur. J. Biochem., 270, 1628-44.
44. Leissring, M.A., Farris, W., Chang, A.Y., Walsh, D.M., Wu, X., Sun, X., Frosch, M.P., Selkoe, D.J. (2003) Enhanced proteolysis of beta-amyloid in APP transgenic mice prevents plaque formation, secondary pathology, and premature death. Neuron, 40, 1087-93.
45. Li, G., Faibushevich, A., Turunen, B.J., Yoon, S.O., Georg, G., Michaelis, M.L., Dobrowsky, R.T. (2003) Stabilization of the cyclin-dependent kinase 5 activator, p35, by paclitaxel decreases beta-amyloid toxicity in cortical neurons. J. Neurochem., 84, 347-62.
46. Li, R., Huang, Y.G., Du, F., Le, W.D. (2004) (-)-Epigallocatechin gallate inhibits lipopolysaccharide-induced microglial activation and protects against inflammation-mediated dopaminergic neuronal injury. J. Neurosci. Res., 78, 723-31.
47. Li, X., Lu, F., Tian, Q., Yang, Y., Wang, Q., Wang, J.Z. (2005) Activation of glycogen synthase kinase-3 induces Alzheimer-like tau hyperphosphorylation in rat hippocampus slices in culture. J. Neural Transm., 113(1), 93-102.
48. Lombardo, J.A., Stern, E.A., Mclellan, M.E., Kajdasz, S.T., Hickey, G.A., Bacskai, B.J., Hyman, B.T. (2003) βAmyloid-antibody treatment leads to rapid normalization of plaque-induced neuritic alterations. J. Neurosci., 23, 10879-10883.
49. Luo, H.M., Deng, H., Xiao, F., Gao, Q., Weng, W., Zhang, P.F., Li, X.G. (2004) Down-regulation amyloid β-protein 42 production by interfering with transcript of presenilin 1 gene with siRNA. Acta Pharmacol. Sin., 25, 1613-1618.
50. Marr, R.A., Rockenstein, E., Mukherjee, A., Kindy, M.S. (2003) Neprilysin gene transfer reduces human amyloid pathology in transgenic mice. J. Neurosci., 23, 1992-1996.
51. Marx, J. (2005) Alzheimer's disease. Play and exercise protect mouse brain from amyloid buildup. Science, 307, 1547.
52. McLaurin, J., Cecal, R., Kierstead, M.E., Tian, X., Phinney, A.L., Manea, M., French, J.E., Lambermon, M.H., Darabie, A.A., Brown, M.E., Janus, C., Chishti, M.A., Horne, P., Westaway, D., Fraser, P.E., Mount, H.T., Przybylski, M., St George-Hyslop, P. (2002) Therapeutically effective antibodies against amyloid-beta peptide target amyloid-beta residues 4-10 and inhibit cytotoxicity and fibrillogenesis. Nat. Med., 8, 1263-9.
53. Michaelis, M.L., Chen, Y., Hill, S., Reiff, E., Georg, G., Rice, A., Audus, K. (2002) Amyloid peptide toxicity and microtubule-stabilizing drugs. J. Mol. Neurosci., 19, 101-5.
54. Michaelis, M.L. (2003) Drugs targeting Alzheimer's disease: some things old and some things new. J. Pharmacol. Exp. Ther., 304, 897-904.
55. Miller,V.M., Gouvion, C.M., Davidson, B.L., Paulson, H.L. (2004) Targeting Alzheimer's disease genes with RNA interference: an effcient strategy for silencing mutant alleles. Nucleic Acids Res., 2, 661-668.
56. Mukherjee, A., Song, E., Kihiko-Ehmann, M., Pyrek, J.S., Estus, S., Hersh, L.B. (2000) Insulysin hydrolyzes amyloid beta peptides to products that are neither neurotoxic nor deposit on amyloid plaques. J. Neurosci., 20, 8745-8749.
57. Nawrot, B. (2004) Targeting β-secretase with small inhibitory nucleic acids - a future for Alzheimer's disease therapy. Acta Biochim. Pol., 51, 431-444.
58. Nicoll, J.A., Wilkinson, D., Holmes, C., Steart, P., Markham, H., Weller, R.O. (2003) Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report. Nat. Med., 9, 448-52.
59. Orgogozo, J.M., Gilman, S., Dartigues, J.F., Laurent, B., Puel, M., Kirby, L.C., Jouanny, P., Dubois, B., Eisner, L., Flitman, S., Michel, B.F., Boada, M., Frank, A., Hock, C. (2003) Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization. Neurology, 61, 46-54.
60. Papasozomenos, Sch., Shanavas, A. (2002) Testosterone prevents the heat shock-induced overactivation of glycogen synthase kinase-3 beta but not of cyclin-dependent kinase 5 and c-Jun NH2-terminal kinase and concomitantly abolishes hyperphosphorylation of tau: implications for Alzheimer's disease. Proc. Natl. Acad. Sci. USA, 99, 1140-5.
61. Permanne, B., Adessi, C., Saborio, G.P., Fraga, S., Frossard, M.J.(2002) Reduction of amyloid load and cerebral damage in a transgenic mouse model of Alzheimer's disease by treatment with a beta-sheet breaker peptide. FASEB J., 16, 860-2.
62. Petit, A., Bihel, F., Alves da Costa, C., Pourquie', O., Kraus, J.L., Checler, F. (2001) New protease inhibitors prevent γ-secretase-mediated Aβ40/42 production without affecting Notch cleavage. Nat. Cell. Biol., 3, 507-511.
63. Pfeifer, M., Boncristiano, S., Bondolfi, L., Stalder, A., Deller, T., Staufenbiel, M., Mathews, P.M., Jucker, M. (2002) Cerebral hemorrhage after passive anti-Abeta mmunotherapy. Science, 298, 1379.
64. Postina, R., Schroedev, A., Dewachter, I., Bohl, J., Schmitt, U., Kojro, E. (2004) A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model. J. Clin. Investig., 13, 1384-1392.
65. Potkin, S.G., Anand, R., Fleming, K. (2001) Brain metabolic and clinical effects of rivastigmine in Alzheimer's disease. Int. J. Neuropsychopharmacol., 4, 223-30.
66. Pratico, D., Clark, C.M., Liun, F., Rokach, J., Lee, V.Y., Trojanowski, J.Q. (2002) Increase of brain oxidative stress in mild cognitive impairment: a possible predictor of Alzheimer disease. Arch. Neurol., 59, 1475.
67. Qu, B., Rosenberg, R.N., Li, L., Boyer, P.J., Johnston, S.A. (2004) Gene vaccination to bias the immune response to amyloid-beta peptide as therapy for Alzheimer disease. Arch. Neurol., 61, 1859-64.
68. Rachakonda, V., Pan, T.H., Le, W.D. (2004) Biomarkers of neurodegenerative disorders: How good are they? Cell. Res., 14, 349-360.
69. Rezai-zadeh, K., Shytle, D., Sun, N., Mori, T., Hou, H., Jeanniton, D., Ehrhart, J., Townsend, K., Zeng, J., Morgan, D., Hardy, J., Town, T., Tan, J. (2005) Green tea epigallocatechin-3-gallate (EGCG) modulates amyloid precursor protein cleavage and reduces cerebral amyloidosis in Alzheimer transgenic mice. J. Neurosci., 25, 8807-14.
70. Rockwood, K., Mintzer, J., Truyen, L., Wessel, T., Wilkinson, D. (2001) Effects of a flexible galantamine dose in Alzheimer??s disease: a randomized, controlled trial. J. Neurol. Neurosurg. Psychiatry, 71, 589-95.
71. Rozemuller, A.J., van Gool, W.A., Eikelenboom, P. (2005) The neuroinflammatory response in plaques and amyloid angiopathy in Alzheimer's disease: therapeutic implications. Curr. Drug Targets CNS. Neurol. Disord., 4, 223-33.
72. Ryder, J., Su, Y., Liu, F., Li, B., Zhou, Y., Ni, B. (2003) Divergent roles of GSK3 and CDK5 in APP Processing. Biochem. Biophys. Res. Commun., 312, 922-9.
73. Schenk, D., Barbour, R., Dunn, W., Gordon, G., Grajeda, H., Guido, T., Hu, K., Huang, J., Johnson-Wood, K., Khan, K. (1999) Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature, 400, 173-177.
74. Siemer, E., Skinner, M., Dean, R.A., Conzales, C., Satterwhite, J., Farlow, M., Ness, D., May, P.C. (2005) Safety, tolerability, and changes in amyloid beta concentrations after administration of a gamma-secretase inhibitor in volunteers. Clin. Neuropharmacol., 28, 126-32.
75. Sigurdsson, E.M., Knudsen, E., Asuni, A., Fitzer-Attas, C., Sage, D., Quartermain, D., Goni, F., Frangione, B., Wisniewski, T. (2004) An attenuated immune response is sufficient to enhance cognition in an Alzheimer's disease mouse model immunized with amyloid-beta derivatives. J. Neurosci., 24, 6277-82.
76. Sigurdsson, E.M., Scholtzova, H., Mehta, P.D., Frangione, B., Wisniewski, T. (2001) Immunization with a nontoxic/nonfibrillar amyloid-beta homologous peptide reduces Alzheimer's disease-associated pathology in transgenic mice. Am. J. Pathol., 159, 439-47.
77. Singer, O., Marr, R.A., Rockenstein, E., Crews, L., Coufal, N.G., Gage, F.H., Verma, I.M., Masliah, E. (2005) Targeting β-secretase1 with siRNAs ameliorates Alzheimer disease neuropathology in a transgenic model. Nat. Neurosci., 8, 1343-1349.
78. Shah, S., Lee, S.F., Tabuchi, K., Hao, Y.H., Yu, C., LaPlant, Q., Ball, H., Sudhof, T., Yu, G. (2005) Nicastrin Functions as a γ-Secretase-Substrate Receptor. Cell, 122, 435-447.
79. Soto, C., Kindy, M.S., Baumann, M., Frangione, B. (1996) Inhibition of Alzheimer's amyloidosis by peptides that prevent beta-sheet conformation. Biochem. Biophys. Res. Commun., 226, 672-680.
80. Soto, C., Sigurdsson, E.M., Morelli, L., Kumar, R.A., Castano, E.M., Frangione, B. (1998) Beta-sheet breaker peptides inhibit fibrillogenesis in a rat brain model of amyloidosis: implications for Alzheimer's therapy. Nat. Med., 4, 822-826.
81. Suh, Y.H., Checler, F. (2002) Amyloid precursor protein, presenilins, and α-synuclein: molecular pathogenesis and pharmacological applications in Alzheimer's disease. Pharmacol. Rev., 54, 469-525.
82. Tanne, J.H. (2005) Activating stem cells may treat Alzheimer's. BMJ, 330, 622.
83. Thinakaran, G., Parent, A.T. (2004) Identification of the role of presenilins beyond Alzheimer's disease. Pharmacol. Res., 50, 411-8.
84. Troy, C.M., Rabacchi, S.A., Hohl, J.B., Angelastro, J.M., Greene, L.A., Shelanski, M.L. (2001) Death in the balance: alternative participation of the caspase-2 and -9 pathways in neuronal death induced by nerve growth factor deprivation. J. Neurosci., 21, 5007-5016.
85. Tuszynski, M.H., Roberts, J., Senut, M.C., U, H.S., Gage, F.H. (1996) Gene therapy in the adult primate brain: intraparenchymal grafts of cells genetically modified to produce nerve growth factor prevent cholinergic neuronal degeneration. Gene Ther., 3, 305-14.
86. Tuszynski, M.H., Thal, L., Pay, M., Salmon, D.P., U, H.S., Bakay, R. (2005) A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease. Nat. Med., 11, 551-5.
87. Tuszynski, M.H., Thal, L., U, H.S., Pay, M.M., Blesch, A., Conner, J., Vahlsing, H.L. (2002) Nerve growth factor gene therapy for Alzheimer's disease. J. Mol. Neurosci., 19, 207.
88. Tyszkiewicz, J.P., Yan, Z. (2005) beta-Amyloid peptides impair PKC-dependent functions of metabotropic glutamate receptors in prefrontal cortical neurons. J. Neurophysiol., 93, 3102-11.
89. Van der Schyf, C.J., Gal, S., Geldenhuys, W.J., Youdim, M.B. (2006) Multi-functional neuroprotective drugs targeting monoamine oxidase inhibition, iron chelation, adenosine receptors, and cholinergic and glutamatergic action for neurodegenerative diseases. Expert Opin. Investig. Drugs, 15(8), 873-86.
90. Walker, E.S., Martinez, M., Brunkan, A.L., Goate, A. (2005) Presenilin 2 familial Alzheimer's disease mutations result in partial loss of function and dramatic changes in Abeta 42/40 ratios. J. Neurochem., 92, 294-301.
91. Wang, Q.H., Xu, R.X. (2005) Transplantation of cholinergic neural stem cells in a mouse model of Alzheimer's disease. Chin. Med. J., 118, 508-511.
92. Weihofen, A., Lemberg, M.K., Friedmann, E., Rueeger, H., Schmitz, A., Paganetti, P., Rovelli, G., Martoglio, B. (2003) Targeting presenilin-type aspartic protease signal peptide peptidase with α-secretase inhibitors. J. Biol. Chem., 278, 16528-16533.
93. Weiner, H.L., Lemere, C.A., Maron, R., Spooner, E.T., Grenfell, T.J., Mori, C., Issazadeh, S., Hancock, W.W., Selkoe, D.J. (2000) Nasal administration of amyloid-beta peptide decreases cerebral amyloid burden in a mouse model of Alzheimer's disease. Ann. Neurol., 48, 567-79.
94. Weksler, M.E. (2004) The immunotherapy of Alzheimer's disease. Immun. Ageing, 1, 2.
95. Yogev-Falach, M., Bar-Am, O., Amit, T., Youdim, M.B. (2006) The multi-functional neuroprotective anti-Alzheimer/anti-Parkinson drug ladostigil (TV3326) regulates holo-APP translation and processing. FASEB J., 20, 2177-2179.
96. Youdim, M.B., Amit, T., Bar-Am, O., Yogev-Falach, M. (2006) Implications of co-morbidity for etiology and treatment of neurodegenerative diseases with multifunctional neuroprotective-neurorescue drugs; ladostigil. Neurotox. Res., 10(2), 1-11.