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Vol. 19, No. 5-6, 2005
Issue release date: May 2005
Dement Geriatr Cogn Disord 2005;19:229–245
(DOI:10.1159/000084400)

Pharmacology of Alzheimer’s Disease: Appraisal and Prospects

Sellal F.a · Nieoullon A.b · Michel G.c · Michel B.F.c · Lacomblez L.d · Geerts H.g · Delini Stula A.h · Bordet R.e · Bentué-Ferrer D.f · Allain H.f
aHôpital Universitaire, Strasbourg, bLaboratoire CNRS – LNCF Neurosciences, and cHôpitaux Sainte Marguerite et de la Conception, Marseille, dFédération Neurologie Mazarin/Service de Pharmacologie, Hôpital de la Pitié Salpétrière, Paris, eLaboratoire de Pharmacologie, Lille, and fLaboratoire de Pharmacologie, Rennes, France; gSilico Biosciences, Philadelphia, Pa., USA; hADI International Institut, Basel, Switzerland
email Corresponding Author

Abstract

Ten years after the introduction of the first drug, tacrine, in the treatment of Alzheimer’s disease, it seems appropriate to reappraise the pharmacological processes of innovation in the research field of dementia. The aim of this review is to pinpoint concrete improvements achieved in this field, regarding experimental methods and clinical evaluation of the compounds, as well as the neurochemistry of the disease and cellular targets to consider in priority. This review deals with this objective in three parts: (1) assessment of current therapeutics, (2) discussion of the experimental models and clinical practices and (3) prospective drugs of the future. The implementation of considered strategies will require the involvement and close cooperation between political decisions, pharmaceutical companies and the scientific community.


 goto top of outline Key Words

  • Alzheimer’s disease
  • Pharmacology
  • Innovation
  • Drug
  • Methodology

 goto top of outline Abstract

Ten years after the introduction of the first drug, tacrine, in the treatment of Alzheimer’s disease, it seems appropriate to reappraise the pharmacological processes of innovation in the research field of dementia. The aim of this review is to pinpoint concrete improvements achieved in this field, regarding experimental methods and clinical evaluation of the compounds, as well as the neurochemistry of the disease and cellular targets to consider in priority. This review deals with this objective in three parts: (1) assessment of current therapeutics, (2) discussion of the experimental models and clinical practices and (3) prospective drugs of the future. The implementation of considered strategies will require the involvement and close cooperation between political decisions, pharmaceutical companies and the scientific community.

Copyright © 2005 S. Karger AG, Basel


 goto top of outline References
  1. Citron M: Strategies for disease modification in Alzheimer’s disease. Nat Rev Neurosci 2004;5:677–685.
  2. Michel BF, Estadieu MC, Gueriot C, Berthezene P, Allain H, Bongrand MC, Bonnefoy B, Bourrin JC, Chaix L, Graa K, Lejeune A, Messana M, Pras P, Ribiere J, Rihet P, Timon- David P, Tintignac A, Vincent S, Verdier JM, Gastaut JL: Traitement de la maladie d’Alzheimer au long cours: à propos d’une cohorte de 255 patients traités quatre ans par tacrine. Rev Neurol (Paris) 2001;11:1365–1375.

    External Resources

  3. Bentué-Ferrer D, Michel B-F, Reymann J-M, Allain H: Les médicaments face à la maladie d’Alzheimer. Revue Gériatr 2001;26:511–522.
  4. Allain H, Bentué-Ferrer D, Tribut O, Belliard S: Drug therapy of fronto-temporal dementia. Hum Psychopharmacol 2003;18:221–225.
  5. Reisberg B, Doody R, Stoffler A, Schmitt F, Ferris S, Mobius HJ; Memantine Study Group: Memantine in moderate-to-severe Alzheimer’s disease. N Engl J Med 2003;348:1333–1341.
  6. Tariot P-N, Farlow M-R, Grossberg G-T, Graham S-M, Mcdonald S, Gergel I: Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: A randomized controlled trial. JAMA 2004;291:317–324.
  7. Lebert M: Slowing the progression of Alzheimer’s disease: Methodologic issues. Alzheimer Dis Assoc Disord 1999;11(suppl 5):510–521.
  8. Allain H, Bentué-Ferrer D, Tribut O, Pinel J-F: Drugs and vascular dementia. Dement Geriatr Cogn Disord 2003;16:1–6.
  9. Lazarewicz M, Spiros A, Finkel L, Carr R, Geerts H: Using a computer simulation of the synapse to understand nicotinic receptor modulation by galantamine. 8th Int Alzheimer Congr, Stockholm, 2002.
  10. Geerts H, Lazarewicz M, Spiros A, Finkel L, Carr R: Galantamine benefits in Alzheimer’s disease are related to increases in dopamine output. Schizophr Res 2003;60(suppl 1):135 (abstr).

    External Resources

  11. Derouesné C: Qu’est ce que la démence? 2. Un concept flou. Psychol Neuropsychiatr Vieil 2003;1:15–24.
  12. Teunissen C-E, De Vente J, Steinbusch H-W-M, De Bruijn C: Biochemical markers related to Alzheimer’s dementia in serum and cerebrospinal fluid. Neurobiol Aging 2002;23:485–508.
  13. Pratico D, Clark C-M, Lee V-M, Trojanowski J-Q, Rokach J, Fitzgerald G-A: Increased 8,12-iso-iPF2alpha-VI in Alzheimer’s disease: Correlation of a noninvasive index of lipid peroxidation with disease severity. Ann Neurol 2000;48:809–812.
  14. Wolf H, Jelic V, Gertz H-J, Nordberg A, Julin P, Wahlund L-O: A critical discussion of the role of neuroimaging in mild cognitive impairment. Acta Neurol Scand 2003(suppl);179:52–76.
  15. Fox N-C, Freeborough P-A: Brain atrophy progression measured from registered serial MRI: Validation and application to Alzheimer’s disease. J Magn Reson Imaging 1997;7:1069–1075.
  16. Fox NC, Cousens S, Scahill R, Harvey RJ, Rossor MN: Using serial registered brain magnetic resonance imaging to measure disease progression in Alzheimer disease. Arch Neurol 2000;57:339–443.
  17. Jack CR Jr, Slomkowski M, Gracon S, Hoover TM, Felmlee JP, Stewart K, Xu Y, Shiung M, O’Brien PC, Cha R, Knopman D, Petersen RC: MRI as a biomarker of disease progression in a therapeutic trial of milameline for Alzheimer’s disease. Neurology 2003;60:253–260.
  18. Valenzuela M-J, Sachdev P: Magnetic resonance spectroscopy in Alzheimer’s disease. Neurology 2001;56:592–598.
  19. Catani M, Cherubini A, Howard R, Tarducci R, Pelliccioli GP, Piccirilli M, Gobbi G, Senin U, Mecocci P: (1)H-MR spectroscopy differentiates mild cognitive impairment from normal aging. Neuroreport 2001;12:2315–2317.
  20. Petrella J-R, Coleman R-E, Doraiswamy P-M: Neuroimaging and early diagnosis of Alzheimer disease: A look of future. Radiology 2003;226:315–336.
  21. Okamura N, Arai H, Maruyama M, Higuchi M, Matsui T, Tanji H, Seki T, Hirai H, Chiba H, Itoh M, Sasaki H: Combined analysis of CSF tau levels and [(131)I] Iodoamphetamine SPECT in mild cognitive impairment: Implications for a novel predictor of Alzheimer’s disease. Am J Psychiatry 2002;159:474–476.
  22. Piolino P: Le vieillissement normal de la mémoire autobiographique. Psychol Neuropsychiatr Vieil 2003;1:25–35.
  23. Quinn J, Moore M, Benson D-F, Clark R, Doody R, Jagust W, Knopman D, Kaye J-A: A videotaped CIBIC for dementia patients. Validity and reliability in a simulated clinical trial. Neurology 2002;58:433–437.
  24. Sramek J-J, Cutler N-R: Recent developments in the drug treatment of Alzheimer’s disease. Drug Aging 1999;14:359–373.
  25. Emilien G, Beyreuther K, Masters C, Maloteaux J-M: Prospects for pharmacological intervention in Alzheimer’s disease. Arch Neurol 2000;57:454–459.
  26. Cutler N-R, Sramek J-J: Review of the next generation of Alzheimer’s disease therapeutics: Challenges for drug development. Prog Neuropsychopharmacol Biol Psychiatry 2001;25:27–57.
  27. Allain H, Bentué-Ferrer D, Tribut O, Gauthier S, Michel B-F, Drieu-La Rochelle C: Alzheimer’s disease: The pharmacological pathway. Fundam Clin Pharmacol 2003;17:419–428.
  28. Scorer CA: Preclinical and clinical challenges in the development of disease-modifying therapies for Alzheimer’s disease. Drug Discov Today 2001;6:1207–1219.
  29. Citron M: Emerging Alzheimer’s disease therapies: Inhibition of β-secretase. Neurobiol Aging 2002;23:1017–1022.
  30. Gandy S: Molecular basis for anti-amyloïd therapy in the prevention and treatment of Alzheimer’s disease. Neurobiol Aging 2002;23:1009–1016.
  31. Kayed R, Head E, Thompson J-L, McIntire TM, Milton SC, Cotman CW, Glabe CG: Common structure of soluble amyloid oligomers implies common mechanisms of pathogenesis. Science 2003;300:486–488.
  32. Hock C, Konietzko U, Streffer J-R, Tracy J, Signorell A, Muller-Tillmanns B, Lemke U, Henke K, Moritz E, Garcia E, Wollmer MA, Umbricht D, de Quervain DJ, Hofmann M, Maddalena A, Papassotiropoulos A, Nitsch RM: Antibodies against beta-amyloid slow cognitive decline in Alzheimer’s disease. Neuron 2003;38:547–554.
  33. Bush A-I: Metal complexing agents as therapies for Alzheimer’s disease. Neurobiol Aging 2002;23:1031–1038.
  34. Regland B, Lehmann W, Abedini I, Blennow K, Jonsson M, Karlsson I, Sjogren M, Wallin A, Xilinas M, Gottfries CG: Treatment of Alzheimer’s disease with clioquinol. Dement Geriatr Cogn Disord 2001;12:408–414.
  35. Castro A, Martinez A: Inhibition of tau phosphorylation: A new therapeutic strategy for the treatment of Alzheimer’s disease and other neurodegenerative disorders. Expert Opin Ther Patents 2000;10:1519–1527.
  36. De Strooper B, Woodgett J: Mental plaque removal. Nature 2003;423:392–393.
  37. McGeer P-L, McGeer E-G: Local neuroinflammation and the progression of Alzheimer’s disease. J Neurovirol 2002;8:529–538.
  38. Smith M-A, Perry G, Atwood C-S, Bowen R-L: Estrogen replacement and risk of Alzheimer disease. JAMA 2003;289:1100.
  39. Nieoullon A: Bases cellulaires des processus neurodégénératifs. Thérapie 1998;53:21–29.
  40. Rothstein J-D, Dykes-Hoberg, Pardo C-A, Bristol L-A, Jin L, Kuncl Rw, Kanai Y, Hediger M-A, Wang Y, Schielke J-P, Weltry F-D: Knock out of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate. Neuron 1996;16:675–686.
  41. Lievens J-C, Bernal F, Forni C, Mahy N, Kerkerian-Le Goff L: Characterization of striatal lesions produced by glutamate uptake alteration: Cell death, reactive gliosis, and changes in GLT1 and GADD45 mRNA expression. Glia 2000;29:222–232.
  42. Had-Aissouni L, Re D-B, Nieoullon A, Kerkerian-Le Goff L: Importance of astrocytic inactivation of synaptically released glutamate for cell survival in the central nervous system – Are astrocytes vulnerable to low intracellular glutamate concentrations? J Physiol (Paris) 2002;96:317–322.
  43. Re D, Boucraut J, Samuel D, Birman S, Kerkerian-Le Goff L, Had-Aissouni L: Glutamate transport alteration triggers differentiation-state selective oxidative death of cultured astrocytes: A mechanism different from excitotoxicity depending on intracellular GSH contents. J Neurochem 2003;85:1159–1170.
  44. Lesh K-P: Gene transfert to the brain: Emerging therapeutic strategy in psychiatry? Biol Psychiatry 2002;45:247–253.

    External Resources

  45. Zhao M, Momma S, Delfani K, Carlen M, Cassidy RM, Johansson CB, Brismar H, Shupliakov O, Frisen J, Janson AM: Evidence for neurogenesis in the adult mammalian substantia nigra. Proc Natl Acad Sci USA 2003;100:7925–7930.
  46. Friedlander RM: Mechanisms of disease: Apoptosis and caspases in neurodegenerative diseases. N Engl J Med 2003;348:1365–1375.
  47. Zhu S, Stavrovskaya IG, Drozda M, Kim BY, Ona V, Li M, Sarang S, Liu AS, Hartley DM, Wu du C, Gullans S, Ferrante RJ, Przedborski S, Kristal BS, Friedlander RM: Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice. Nature 2002;417:74–78.
  48. Li M, Ona VO, Guegan C, Chen M, Jackson-Lewis V, Andrews LJ, Olszewski AJ, Stieg PE, Lee JP, Przedborski S, Friedlander RM: Functional role of caspase 1 and caspase 3 in ALS transgenic mouse model. Science 2000;288:335–339.
  49. Mattson MP: Pathways towards and away from Alzheimer’s disease. Nature 2004;430:631–639.
  50. Lebrun C: Le futur comme objet de désir. Futuribles 2003;286:29–42.

 goto top of outline Author Contacts

Danièle Bentué-Ferrer
Department of Pharmacology, Faculté de Médecine, University of Rennes I
2, avenue du Professeur Léon-Bernard, FR–35043 Rennes (France)
Tel. +33 2 23 23 47 13, Fax +33 2 23 23 46 05
E-Mail daniele.bentue-ferrer@univ-rennes1.fr


 goto top of outline Article Information

Accepted: October 30, 2004
Published online: March 11, 2005
Number of Print Pages : 17
Number of Figures : 2, Number of Tables : 1, Number of References : 50


 goto top of outline Publication Details

Dementia and Geriatric Cognitive Disorders

Vol. 19, No. 5-6, Year 2005 (Cover Date: May-June 2005)

Journal Editor: Chan-Palay, V. (New York, N.Y.)
ISSN: 1420–8008 (print), 1421–9824 (Online)

For additional information: http://www.karger.com/dem


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

Ten years after the introduction of the first drug, tacrine, in the treatment of Alzheimer’s disease, it seems appropriate to reappraise the pharmacological processes of innovation in the research field of dementia. The aim of this review is to pinpoint concrete improvements achieved in this field, regarding experimental methods and clinical evaluation of the compounds, as well as the neurochemistry of the disease and cellular targets to consider in priority. This review deals with this objective in three parts: (1) assessment of current therapeutics, (2) discussion of the experimental models and clinical practices and (3) prospective drugs of the future. The implementation of considered strategies will require the involvement and close cooperation between political decisions, pharmaceutical companies and the scientific community.



 goto top of outline Author Contacts

Danièle Bentué-Ferrer
Department of Pharmacology, Faculté de Médecine, University of Rennes I
2, avenue du Professeur Léon-Bernard, FR–35043 Rennes (France)
Tel. +33 2 23 23 47 13, Fax +33 2 23 23 46 05
E-Mail daniele.bentue-ferrer@univ-rennes1.fr


 goto top of outline Article Information

Accepted: October 30, 2004
Published online: March 11, 2005
Number of Print Pages : 17
Number of Figures : 2, Number of Tables : 1, Number of References : 50


 goto top of outline Publication Details

Dementia and Geriatric Cognitive Disorders

Vol. 19, No. 5-6, Year 2005 (Cover Date: May-June 2005)

Journal Editor: Chan-Palay, V. (New York, N.Y.)
ISSN: 1420–8008 (print), 1421–9824 (Online)

For additional information: http://www.karger.com/dem


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Citron M: Strategies for disease modification in Alzheimer’s disease. Nat Rev Neurosci 2004;5:677–685.
  2. Michel BF, Estadieu MC, Gueriot C, Berthezene P, Allain H, Bongrand MC, Bonnefoy B, Bourrin JC, Chaix L, Graa K, Lejeune A, Messana M, Pras P, Ribiere J, Rihet P, Timon- David P, Tintignac A, Vincent S, Verdier JM, Gastaut JL: Traitement de la maladie d’Alzheimer au long cours: à propos d’une cohorte de 255 patients traités quatre ans par tacrine. Rev Neurol (Paris) 2001;11:1365–1375.

    External Resources

  3. Bentué-Ferrer D, Michel B-F, Reymann J-M, Allain H: Les médicaments face à la maladie d’Alzheimer. Revue Gériatr 2001;26:511–522.
  4. Allain H, Bentué-Ferrer D, Tribut O, Belliard S: Drug therapy of fronto-temporal dementia. Hum Psychopharmacol 2003;18:221–225.
  5. Reisberg B, Doody R, Stoffler A, Schmitt F, Ferris S, Mobius HJ; Memantine Study Group: Memantine in moderate-to-severe Alzheimer’s disease. N Engl J Med 2003;348:1333–1341.
  6. Tariot P-N, Farlow M-R, Grossberg G-T, Graham S-M, Mcdonald S, Gergel I: Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: A randomized controlled trial. JAMA 2004;291:317–324.
  7. Lebert M: Slowing the progression of Alzheimer’s disease: Methodologic issues. Alzheimer Dis Assoc Disord 1999;11(suppl 5):510–521.
  8. Allain H, Bentué-Ferrer D, Tribut O, Pinel J-F: Drugs and vascular dementia. Dement Geriatr Cogn Disord 2003;16:1–6.
  9. Lazarewicz M, Spiros A, Finkel L, Carr R, Geerts H: Using a computer simulation of the synapse to understand nicotinic receptor modulation by galantamine. 8th Int Alzheimer Congr, Stockholm, 2002.
  10. Geerts H, Lazarewicz M, Spiros A, Finkel L, Carr R: Galantamine benefits in Alzheimer’s disease are related to increases in dopamine output. Schizophr Res 2003;60(suppl 1):135 (abstr).

    External Resources

  11. Derouesné C: Qu’est ce que la démence? 2. Un concept flou. Psychol Neuropsychiatr Vieil 2003;1:15–24.
  12. Teunissen C-E, De Vente J, Steinbusch H-W-M, De Bruijn C: Biochemical markers related to Alzheimer’s dementia in serum and cerebrospinal fluid. Neurobiol Aging 2002;23:485–508.
  13. Pratico D, Clark C-M, Lee V-M, Trojanowski J-Q, Rokach J, Fitzgerald G-A: Increased 8,12-iso-iPF2alpha-VI in Alzheimer’s disease: Correlation of a noninvasive index of lipid peroxidation with disease severity. Ann Neurol 2000;48:809–812.
  14. Wolf H, Jelic V, Gertz H-J, Nordberg A, Julin P, Wahlund L-O: A critical discussion of the role of neuroimaging in mild cognitive impairment. Acta Neurol Scand 2003(suppl);179:52–76.
  15. Fox N-C, Freeborough P-A: Brain atrophy progression measured from registered serial MRI: Validation and application to Alzheimer’s disease. J Magn Reson Imaging 1997;7:1069–1075.
  16. Fox NC, Cousens S, Scahill R, Harvey RJ, Rossor MN: Using serial registered brain magnetic resonance imaging to measure disease progression in Alzheimer disease. Arch Neurol 2000;57:339–443.
  17. Jack CR Jr, Slomkowski M, Gracon S, Hoover TM, Felmlee JP, Stewart K, Xu Y, Shiung M, O’Brien PC, Cha R, Knopman D, Petersen RC: MRI as a biomarker of disease progression in a therapeutic trial of milameline for Alzheimer’s disease. Neurology 2003;60:253–260.
  18. Valenzuela M-J, Sachdev P: Magnetic resonance spectroscopy in Alzheimer’s disease. Neurology 2001;56:592–598.
  19. Catani M, Cherubini A, Howard R, Tarducci R, Pelliccioli GP, Piccirilli M, Gobbi G, Senin U, Mecocci P: (1)H-MR spectroscopy differentiates mild cognitive impairment from normal aging. Neuroreport 2001;12:2315–2317.
  20. Petrella J-R, Coleman R-E, Doraiswamy P-M: Neuroimaging and early diagnosis of Alzheimer disease: A look of future. Radiology 2003;226:315–336.
  21. Okamura N, Arai H, Maruyama M, Higuchi M, Matsui T, Tanji H, Seki T, Hirai H, Chiba H, Itoh M, Sasaki H: Combined analysis of CSF tau levels and [(131)I] Iodoamphetamine SPECT in mild cognitive impairment: Implications for a novel predictor of Alzheimer’s disease. Am J Psychiatry 2002;159:474–476.
  22. Piolino P: Le vieillissement normal de la mémoire autobiographique. Psychol Neuropsychiatr Vieil 2003;1:25–35.
  23. Quinn J, Moore M, Benson D-F, Clark R, Doody R, Jagust W, Knopman D, Kaye J-A: A videotaped CIBIC for dementia patients. Validity and reliability in a simulated clinical trial. Neurology 2002;58:433–437.
  24. Sramek J-J, Cutler N-R: Recent developments in the drug treatment of Alzheimer’s disease. Drug Aging 1999;14:359–373.
  25. Emilien G, Beyreuther K, Masters C, Maloteaux J-M: Prospects for pharmacological intervention in Alzheimer’s disease. Arch Neurol 2000;57:454–459.
  26. Cutler N-R, Sramek J-J: Review of the next generation of Alzheimer’s disease therapeutics: Challenges for drug development. Prog Neuropsychopharmacol Biol Psychiatry 2001;25:27–57.
  27. Allain H, Bentué-Ferrer D, Tribut O, Gauthier S, Michel B-F, Drieu-La Rochelle C: Alzheimer’s disease: The pharmacological pathway. Fundam Clin Pharmacol 2003;17:419–428.
  28. Scorer CA: Preclinical and clinical challenges in the development of disease-modifying therapies for Alzheimer’s disease. Drug Discov Today 2001;6:1207–1219.
  29. Citron M: Emerging Alzheimer’s disease therapies: Inhibition of β-secretase. Neurobiol Aging 2002;23:1017–1022.
  30. Gandy S: Molecular basis for anti-amyloïd therapy in the prevention and treatment of Alzheimer’s disease. Neurobiol Aging 2002;23:1009–1016.
  31. Kayed R, Head E, Thompson J-L, McIntire TM, Milton SC, Cotman CW, Glabe CG: Common structure of soluble amyloid oligomers implies common mechanisms of pathogenesis. Science 2003;300:486–488.
  32. Hock C, Konietzko U, Streffer J-R, Tracy J, Signorell A, Muller-Tillmanns B, Lemke U, Henke K, Moritz E, Garcia E, Wollmer MA, Umbricht D, de Quervain DJ, Hofmann M, Maddalena A, Papassotiropoulos A, Nitsch RM: Antibodies against beta-amyloid slow cognitive decline in Alzheimer’s disease. Neuron 2003;38:547–554.
  33. Bush A-I: Metal complexing agents as therapies for Alzheimer’s disease. Neurobiol Aging 2002;23:1031–1038.
  34. Regland B, Lehmann W, Abedini I, Blennow K, Jonsson M, Karlsson I, Sjogren M, Wallin A, Xilinas M, Gottfries CG: Treatment of Alzheimer’s disease with clioquinol. Dement Geriatr Cogn Disord 2001;12:408–414.
  35. Castro A, Martinez A: Inhibition of tau phosphorylation: A new therapeutic strategy for the treatment of Alzheimer’s disease and other neurodegenerative disorders. Expert Opin Ther Patents 2000;10:1519–1527.
  36. De Strooper B, Woodgett J: Mental plaque removal. Nature 2003;423:392–393.
  37. McGeer P-L, McGeer E-G: Local neuroinflammation and the progression of Alzheimer’s disease. J Neurovirol 2002;8:529–538.
  38. Smith M-A, Perry G, Atwood C-S, Bowen R-L: Estrogen replacement and risk of Alzheimer disease. JAMA 2003;289:1100.
  39. Nieoullon A: Bases cellulaires des processus neurodégénératifs. Thérapie 1998;53:21–29.
  40. Rothstein J-D, Dykes-Hoberg, Pardo C-A, Bristol L-A, Jin L, Kuncl Rw, Kanai Y, Hediger M-A, Wang Y, Schielke J-P, Weltry F-D: Knock out of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate. Neuron 1996;16:675–686.
  41. Lievens J-C, Bernal F, Forni C, Mahy N, Kerkerian-Le Goff L: Characterization of striatal lesions produced by glutamate uptake alteration: Cell death, reactive gliosis, and changes in GLT1 and GADD45 mRNA expression. Glia 2000;29:222–232.
  42. Had-Aissouni L, Re D-B, Nieoullon A, Kerkerian-Le Goff L: Importance of astrocytic inactivation of synaptically released glutamate for cell survival in the central nervous system – Are astrocytes vulnerable to low intracellular glutamate concentrations? J Physiol (Paris) 2002;96:317–322.
  43. Re D, Boucraut J, Samuel D, Birman S, Kerkerian-Le Goff L, Had-Aissouni L: Glutamate transport alteration triggers differentiation-state selective oxidative death of cultured astrocytes: A mechanism different from excitotoxicity depending on intracellular GSH contents. J Neurochem 2003;85:1159–1170.
  44. Lesh K-P: Gene transfert to the brain: Emerging therapeutic strategy in psychiatry? Biol Psychiatry 2002;45:247–253.

    External Resources

  45. Zhao M, Momma S, Delfani K, Carlen M, Cassidy RM, Johansson CB, Brismar H, Shupliakov O, Frisen J, Janson AM: Evidence for neurogenesis in the adult mammalian substantia nigra. Proc Natl Acad Sci USA 2003;100:7925–7930.
  46. Friedlander RM: Mechanisms of disease: Apoptosis and caspases in neurodegenerative diseases. N Engl J Med 2003;348:1365–1375.
  47. Zhu S, Stavrovskaya IG, Drozda M, Kim BY, Ona V, Li M, Sarang S, Liu AS, Hartley DM, Wu du C, Gullans S, Ferrante RJ, Przedborski S, Kristal BS, Friedlander RM: Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice. Nature 2002;417:74–78.
  48. Li M, Ona VO, Guegan C, Chen M, Jackson-Lewis V, Andrews LJ, Olszewski AJ, Stieg PE, Lee JP, Przedborski S, Friedlander RM: Functional role of caspase 1 and caspase 3 in ALS transgenic mouse model. Science 2000;288:335–339.
  49. Mattson MP: Pathways towards and away from Alzheimer’s disease. Nature 2004;430:631–639.
  50. Lebrun C: Le futur comme objet de désir. Futuribles 2003;286:29–42.