Strategies for disease modification in Alzheimer's disease

Nature Reviews Neuroscience

Volumn 5, Issue 9, 2004, Pages 677-685

  Citron, Martin ^a  

^a M/S29 2 B ^*  (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALPHA SECRETASE; ALZHEIMER DISEASE VACCINE; AMYLOID BETA PROTEIN; AMYLOID PRECURSOR PROTEIN; ANTILIPEMIC AGENT; BETA SECRETASE; CLIOQUINOL; CYCLIN DEPENDENT KINASE 5; GAMMA SECRETASE; GAMMA SECRETASE INHIBITOR; GLYCOSAMINOGLYCAN; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; MUSCARINIC M1 RECEPTOR AGONIST; NAPROXEN; NERVE GROWTH FACTOR; NONSTEROID ANTIINFLAMMATORY AGENT; TAU PROTEIN;

ALZHEIMER DISEASE; ANIMAL MODEL; ANTIBODY TITER; ANTIINFLAMMATORY ACTIVITY; CENTRAL NERVOUS SYSTEM; CLINICAL ARTICLE; CLINICAL TRIAL; COGNITION; CONTROLLED CLINICAL TRIAL; CONTROLLED STUDY; DOUBLE BLIND PROCEDURE; DRUG EFFECT; DRUG TARGETING; ENZYME INHIBITION; HUMAN; HUMAN TISSUE; HYPERCHOLESTEROLEMIA; IMMUNOTHERAPY; MICROGLIA; MOUSE; MULTICENTER STUDY; NEUROLOGIC DISEASE; NEUROPATHOLOGY; NEUROPHARMACOLOGY; NONHUMAN; PASSIVE IMMUNIZATION; PHAGOCYTOSIS; PHASE 1 CLINICAL TRIAL; PHASE 2 CLINICAL TRIAL; PHASE 3 CLINICAL TRIAL; PRIORITY JOURNAL; PROTEIN PROTEIN INTERACTION; RANDOMIZED CONTROLLED TRIAL; REVIEW; TREATMENT OUTCOME;

ALZHEIMER DISEASE; ANIMALS; DISEASE MANAGEMENT; HUMANS;

ANIMALIA;

EID: 4344580888     PISSN: 1471003X     EISSN: None     Source Type: Journal    
DOI: 10.1038/nrn1495     Document Type: Review

References (95)

1. Davis, K. L. & Samuels, S. C. in Pharmacological Management of Neurological and Psychiatric Disorders (eds Enna, S. J. & Coyle, J. T.) 267-316 (McGraw-Hill, New York, 1998).
2. Doody, R. S. Therapeutic standards in Alzheimer disease. Alzheimer Dis. Assoc. Disord. 13 (Suppl.), 20-26 (1999).
3. Ferris, S. H. Evaluation of memantine for the treatment of Alzheimer's disease. Expert Opin. Pharmacother. 4, 2305-2313 (2003).
4. Hardy, J. & Selkoe, D. J. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297, 353-356 (2002). An updated summary of the amyloid hypothesis.
5. Wash, D. M. et al. Naturally secreted oligomers of amyloid protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416, 535-539 (2002).
6. Gong, Y. et al. Alzheimer's disease-affected brain: presence of oligomeric Aβ ligands (ADDLs) suggests a molecular basis for reversible memory loss. Proc. Natl Acad. Sci. USA 100, 10417-10422 (2003).
7. Drews, J. Drug discovery: a historical perspective. Science 287, 1960-1964 (2000).
8. Cherny, R. A. 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).
9. Ritchie, C. W. et al. Metal-protein attenuation with iodochlorhydroxyquin (dioquinol) targeting Aβ amyloid deposition and toxicity in Alzheimer disease. Arch. Neurol. 60, 1685-1691 (2003).
10. Schenk, D. et al. Immunization with amyloid-β attenuates Alzheimer-disease-liKe pathology in the PDAPP mouse. Nature 400, 173-177 (1999). The first publication on a vaccination approach for AD.
11. Morgan, D, et al. Aβ peptide vaccination prevents memory loss in an animal model of Alzheimers disease. Nature 408, 982-985 (2000).
12. Janus, C. et al. Aβ peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease. Nature 408, 979-982 (2000).
13. Hrncic, R. et al. Antibody-mediated resolution of light chain-associated amyloid deposits. Am. J. Pathol. 157, 1239-1246 (2000).
14. Bard, F. et al. Peripherally administered antibodies against amyloid β-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nature Med. 6, 916-919 (2000).
15. Poduslo, J. F., Curran, G. L., Wengenack, T. M., Malester, B. & Duff, K. Permeability of proteins at the blood-brain barrier in the normal adult mouse and double transgenic mouse model of Alzheimers disease. Neurobiol. Dis. 8, 555-567 (2001).
16. Sturchler-Pierrat, C. et al. Two amyloid precursor protein transgenic mouse models with Alzheimer's disease like pathology. Proc. Natl Acad. Sci. USA 94, 13287-13292 (1997).
17. Winkler, D. T. et al. Spontaneous hemorrhagic stroke in a mouse model of cerebral amyloid angiopathy. J. Neurosci. 21, 1619-1627 (2001).
18. Pfeifer, M. et al. Cerebral hemorrhage after passive anti-Aβ immunotherapy. Science 298, 1379 (2002).
19. Bard, F. et al. Epitope and isotype specificities of antibodies to β-amyloid peptide for protection against Alzheimer's disease like neuropathology. Proc. Natl Acad. Sci. USA 100, 2023-2028 (2003).
20. Monsonego, A. Immunogenic aspects of amyloid β-peptide: implications for pathogenesis and treatment of Alzheimers disease. Neurobiol. Aging 23 (Suppl.), 112 (2002).
21. Frenkel, D., Katz, O. & Solomon, B. Immunization against Alzheimer's β-amyloid plaques via EFRH phage administration. Proc. Natl Acad. Sci. USA 97, 11455-11459 (2000).
22. DeMattos, R. B. et al. Peripheral anti-Aβ antibody alters CNS and plasma Aβ clearance and decreases brain Aβ burden in a mouse model of Alzheimer's disease. Proc. Natl Acad. Sci. USA 98, 8850-8855 (2001).
23. Dodart, J. C. et al. Immunization reverses memory deficits without reducing brain Aβ burden in Alzheimer's disease model. Nature Neurosci. 5, 452-457 (2002).
24. Orgogozo, J. M. et al. Subacute meningoencephalitis in a subset of patients with AD after Aβ42 vaccination. Neurology 61, 46-54 (2003).
25. Nicoll, J. A. R. et al. Neuropathology of human Alzheimer disease after immunization with amyloid-β peptide: a case report. Nature Med. 9, 448-452 (2003). First report to indicate that anti-Aβ immunotherapy reduces plaque pathology in humans.
26. Ferrer, I., Rovira, M. B., Guerra, M. L. S., Rey, M. J. & Costa-Jussa, F. Neuropathology and pathogenesis of encephalitis following amyloid-β immunization in Alzheimer's disease. Brain Pathol. 14, 11-20 (2004).
27. Hock, C. et al. Antibodies against β-amyloid slow cognitive decline in Alzheimer's disease. Neuron 38, 547-554 (2003).
28. Nitsch, R. M., Slack, B. E., Wurtman, R. J. & Growdon, J. H. Release of Alzheimer amyloid precursor derivatives stimulated by activation of muscarinic acetylcholine receptors. Science 258, 304-307 (1992). First demonstration that muscarinic agents can modulate APP processing.
29. Buxbaum, J. D. et al. Cholinergic agonists and interteukin 1 regulate processing and secretion of the Alzheimer β/A4 amyloid precursor protein. Proc. Natl Acad. Sci. USA 89, 3055-3059 (1992).
30. Fisher, A. M1 muscarinic agonists: their potential in treatment and as disease-modifying agents in Alzheimer's disease. Drug Dev. Res. 50, 291-297 (2000).
31. Hock, C. et al. Treatment with the selective muscarinic m1 agonist talsaclidine decreases cerebrospinal fluid levels of Aβ42 in patients with Alzheimer's disease. Amyloid 10, 1-6 (2003).
32. Haass, C. et al. Amyloid β-peptide is produced by cultured cells during normal metabolism. Nature 359, 322-325 (1992).
33. Shoji, M. et al. Production of the Alzheimer amyloid β protein by normal proteolytic processing. Science 258, 126-129 (1992).
34. Dovey, H. F. et al. Functional γ-secretase inhibitors reduce β-amyloid peptide levels in brain. J. Neurochem. 76. 173-181 (2001).
35. Lanz, T. A. et al. The γ-secretase inhibitor N-[N-(3,5- Difluorophenacetyl)-L-alanyl)-S-phenylglycinet-butyl ester reduces Aβ levels in vivo in plasma and cerebrospinal fluid in young (plaque-free) and aged (plaque bearing) Tg2576 mice. J. Pharmacol. Exp. Ther. 305, 864-871 (2003).
36. Siemers, E. R. et al. in 56th Annual Meeting of the American Academy of Neurology abstr. S17.001 (San Francisco, USA, 2004).
37. DeStrooper, B. Aph-1, Pen-2, and Nicastrin with Presenilin generate an active γ-secretase complex. Neuron 38, 9-12 (2003). Recent review of the complex biology of γ-secretase.
38. Edbauer, D. et al. Reconstitution of γ-secretase activity. Nature Cell Biol. 5, 486-488 (2003).
39. DeStrooper, B. et al. A presenilin-1-dependent γ-secretase-like protease mediates release of Notch intracellular domain. Nature 398, 518-522 (1999). Demonstration that Notch signalling depends on γ-secretase activity, affecting the development of γ-secretase inhibitor drugs.
40. Hadland, B. K. et al. γ-secretase inhibitors repress thymocyte development. Proc. Natl Acad. Sci. USA 98, 7487-7491 (2001).
41. Doerfler, P., Shearman, M. S. & Perlmutter, R. M. Presenilin-dependent γ-secretase activity modulates thymocyte development. Proc. Natl Acad. Sci. USA 98, 9312-9317 (2001).
42. Wong, G. T. et al. Chronic treatment with the γ-secretase inhibitor LY-411,575 inhibits β-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation. J. Biol. Chem. 279, 12876-12882 (2004).
43. Jarrett, J. T., Berger, E. P. & Lansbury, P. T. Jr. The carboxy terminus of the β amyloid protein is critical for the seeding of amyloid formation: implications for the pathogenesis of Alzheimer's disease. Biochemistry 32, 4693-4697 (1993).
44. Weggen, S. et al. A subset of NSAIDs lower amyloidogenic Aβ42 independently of cyclooxygenase activity. Nature 414, 212-216 (2001). First publication to show an Aβ42 lowering effect of certain NSAIDs.
45. Sagi, S., Weggen, S., Eriksen, J. L., Golde, T. E. & Koo, E. H. The non-cyclooxygenase targets of non-steroidal anti-inflammatory drugs, lipoxygenases, peroxisome proliferator-activated receptor, inhibitor of κB kinase, and NFκB, do not reduce amyloid β42 production. J. Biol. Chem. 278, 31825-31830 (2003).
46. Weggen, S. et al. Evidence that nonsteroidal anti-inflammatory drugs decrease amyloid β42 production by direct modulation of γ-secretase activity. J. Biol. Chem. 278, 31831-31837 (2003).
47. Wolfe, M. S. et al. Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and γ-secretase activity. Nature 398, 513-517 (1999).
48. Vassar, R. et al. β-Secretase cleavage of AlzheimerS amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286, 735-741 (1999). First identification of β-secretase.
49. Sinha, S. et al. Purification and cloning of amyloid precursor protein β-secretase from human brain. Nature 402, 537-540 (1999).
50. Yan, R. et al. Membrane-anchored aspartyl protease with Alzheimer's disease β-secretase specificity. Nature 402, 533-537 (1999).
51. Hussain, I. et al. Identification of a novel aspartic protease (Asp2) as β-secretase. Mol. Cell. Neurosci. 14, 419-427 (1999).
52. Saunders, A. J. et al. BACE maps to chromosome 11 and a BACE homolog, BACE2, resides in the obligate Down syndrome region of chromosome 21. Science 286, 1255 (1999).
53. Citron, M. β-secretase inhibition for the treatment of Alzheimer's disease - promise and challenge. Trends Phamacol. Sci. 25, 59-112 (2004).
54. Holsinger, R. M. D., McLean, C. A., Beyreuther, K., Masters, C. L. & Evin, G. Increased expression of the amyloid precursor β-secretase in sporadic Alzheimer's disease. Ann. Neurol. 51, 783-786 (2002).
55. Fukumoto, H., Cheung, B. S., Hyman, B. T. & Irizarry, M. C. β-Secretase protein and activity are increased in the neocortex in Alzheimer disease. Arch. Neurol. 59, 1381-1389 (2002).
56. Yang, L. B. et al. Elevated β-secretase expression and enzymatic activity detected in sporadic Alzheimer disease. Nature Med. 9, 3-4 (2003).
57. Li, R. et al. Amyloid β peptide load is correlated with increased β-secretase activity in sporadic Alzheimers disease patients. Proc. Natl Acad. Sci. USA 101, 3632-3637 (2004).
58. Zambrowicz, B. P. & Sands, A. T. Knockouts model the 100 best-selling drugs - will they model the next 100? Nature Rev. Drug Discov. 2, 38-51 (2003).
59. Luo, Y. et al. Mice deficient in BACE1, the Alzheimer's β-secretase, have normal phenotype and abolished β-amyloid generation. Nature Neurosci. 4, 231-232 (2001).
60. Cai, H. et al. BACE1 is the major β-secretase for generation of Aβ peptides by neurons. Nature Neurosci. 4, 233-234 (2001).
61. Roberds, S. L. et al. BACE knockout mice are healthy despite lacking the primary β-secretase activity in brain: implications for Alzheimer's disease therapeutics. Hum. Mol. Genet 10, 1317-1324 (2001).
62. Turner, R. T. et al. Subsite specificity of memapsin 2 (β-secretase): implications for inhibitor design. Biochemistry 40, 10001-10006 (2001).
63. Kitazume, S. et al. Alzheimer's β-secreiase, β-site amyloid precursor protein cleaving enzyme, is responsible for cleavage secretion of a Golgi-resident sialyltransferase. Proc. Natl Acad. Sci. USA 98, 13554-13559 (2001).
64. Kitazume, S. et al. Characterization of α2,6-sialyltransferase cleavage by Alzheimer's β-secretase (BACE1). J. Biol. Chem. 278, 14865-14871 (2003).
65. Lichtenthaler, S. et al. The cell adhesion protein P-selectin glycoprotein ligand-1 is a substrate for the aspartyl protease BACE1. J. Biol. Chem. 278, 48713-48719 (2003).
66. Luo, Y. et al. BACE1 (β-secretase) knockout mice do not acquire compensatory gene expression changes or develop neural lesions over time. Neurobiol. Dis. 14, 81-88 (2003).
67. Harrison, S. M. et al. BACE1 (β-secretase) transgenic and knockout mice: identification of neurochemical deficits and behavioral changes. Mol. Cell. Neurosci. 24, 646-655 (2003).
68. Hsiao, K. et al. Correlative memory deficits, Aβ elevation, and amyloid plaques in transgenic mice. Science 274, 99-102 (1996).
69. Onno, M. et al. BACE1 deficiency rescues memory deficits and cholinergic dysfunction in a mouse model of Alzheimer's disease. Neuron 41, 27-33 (2004).
70. John, V., Beck, J. P., Bienkowski, M. J., Sinha, S. & Heinrikson, R. L. Human β-secretase (BACE) and BACE inhibitors. J. Med. Chem. 46, 4625-4630 (2003).
71. Leung, D., Abbenante, G. & Fairlie, D. P. Protease inhibitors: current status and future prospects. J. Med. Chem. 43, 305-341 (2000).
72. Hong, L. et al. Structure of the protease domain of memapsin 2 (β-secretase) complexed with inhibitor. Science 290, 150-153 (2000). Crystal structure of β-secretase, which was crucial for rational inhibitor design.
73. McGeer, P. L. & McGeer, E. G. Inflammation, autotoxicity and Alzheimer's disease. Neurobiol. Aging 22, 799-809 (2001).
74. McGeer, P. L., Schulzer, M. & McGeer, E. G. Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer's disease: a review of 17 epidemiological studies. Neurology 47, 425-432 (1996).
75. Rogers, J. et al. Clinical trial of indomethacin in Alzheimer's disease. Neurology 43, 1609-1611 (1993).
76. Sainali, S. M., Ingram, D. M. & Talwaker, S. in 6th International Stockholm-Springfield Symposium on Advances in Alzheimer Therapy Abstr. (Stockholm, 2000).
77. Aisen, P. S. et al. Effects of rofecoxib or naproxen vs placebo on Alzheimer disease progression: a randomized controlled trial. JAMA 289, 2819-2826 (2003).
78. Lim, G. P. et al. Ibuprofen suppresses plaque pathology and inflammation in a mouse model for Alzheimer's disease. J. Neurosci. 20, 5709-5714 (2000).
79. Van, Q. et al. Anti-inflammatory drug therapy alters β-amyloid processing and deposition in an animal model of Alzheimer's disease. J. Neurosci. 23, 7504-7509 (2003).
80. Jick, H., Zomberg, G. L., Jick, S. S., Seshadri, S. & Drachman, D. A. Statins and the risk of dementia. Lancet 356, 1627-1631 (2000).
81. Wolozin, B., Kellman, W., Ruosseau, P., Celesia, G. G. & Siegel, G. Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3- methyglutaryl coenzyme A reductase inhibitors. Arch. Neurol. 57, 1439-1443 (2000).
82. Corder, E. H. et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 261, 921-923 (1993).
83. Sing, C. F. & Davignon, J. Role of the apolipoprotein E polymorphism in determining normal plasma lipid and lipoprotein variation. Am. J. Hum. Genet. 37, 268-285 (1985).
84. Wolozin, B. Cholesterol and the biology of Alzheimer's disease. Neuron 41, 7-10 (2004).
85. Puglielli, L. et al. Acyl-coenzyme A: cholesterol acyltransferase modulates the generation of the amyloid β-peptide. Nature Cell Biol. 3, 905-912 (2001).
86. Adamson, P. & Greenwood, J. How do statins control neuroinflammation? Inflam. Res. 52, 399-403 (2003).
87. Jonhagen, M. E. et al. Intracerebroventricular infusion of nerve growth factor in three patients with Alzheimer's disease. Dementia Geriat. Cogn. Disord. 9, 246-257 (1998).
88. Tuszynski, M. H. et al. in 56th Annual Meeting of the American Academy of Neurology abstr. S17.002 (San Francisco, USA, 2004).
89. Moller, H. J. Reappraising neurotransmitter based strategies. Eur. Neuropsychopharmacol. 9 (Suppl.), 53-59 (1999).
90. Gill, S. S. et al. Direct brain infusion of glial cell line-derived neurotrophic factor in Parkinson's disease. Nature Med. 9, 589-595 (2003).
91. Arriagada, P. V., Growdon, J. H., Hedley-White, E. T. & Hyman, B. T. Neurofibrillary tangles, but not senile plaques parallel duration and severity of Alzheimer's disease. Neurology 42, 631-639 (1992).
92. Lee, V. M. Y. & Trojanowski, J. Q. Neurodegenerative tauopathies: human disease and transgenic mouse models. Neuron 24, 507-510 (1999).
93. Lewis, J. et al. Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein. Nature Genet. 25, 402-405 (2000).
94. Noble, W. et al. Cdk5 is a key factor in tau aggregation and tangle formation in vivo. Neuron 38, 555-565 (2003).
95. Hardy, J. & Allsop, D. Amyloid deposition as the central event in the aetiology of Alzheimer's disease. Trends Pharmacol. Sci. 12, 383-388 (1991).