Skip to main content

Advertisement

SpringerLink
Log in

The role of the N-methyl-D-aspartate receptor in Alzheimer’s disease: Therapeutic potential

  • Published:
Current Neurology and Neuroscience Reports Aims and scope Submit manuscript

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with an unknown etiology. Pathologic processes implicated in AD include β-amyloid-induced synaptic failure; tau hyperphosphorylation; inflammation; oxidative stress; abnormal neurotransmission involving acetylcholine, glutamate, norepinephrine, serotonin, and dopamine; and abnormalities in second messengers, protein kinases, and apoptosis. Although each of these pathways offers potential therapeutic targets, pharmacologic manipulation of the glutamatergic N-methyl-D-aspartate receptor pathway, alone or in combination with cholinergic therapies, is emerging as the next promising strategy for the treatment of AD and vascular dementia.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References and Recommended Reading

  1. Danysz W, Parsons C, Möbius HJ, et al.: Neuroprotective and symptomatological action of memantine relevant for Alzheimer’s diesease—a unified glutamatergic hypothesis on the mechanism of action. Neurotoxicity Res 1999, 2:85–97.

    Article  Google Scholar 

  2. Collingridge GL, Kehl SJ, McLennan H: Excitatory amino acids in synaptic transmission in the Schaffer collateralcommissural pathway of the rat hippocampus. J Physiol 1983, 334:33–46.

    PubMed  CAS  Google Scholar 

  3. Frankiewicz T, Potier B, Bashir ZI, et al.: Effects of memantine and MK-801 on NMDA-induced currents in cultured neurones and on synaptic transmission and LTP in area CA1 of rat hippocampal slices. Br J Pharmacol 1996, 117:689–697.

    PubMed  CAS  Google Scholar 

  4. Morris RG, Anderson E, Lynch GS, Baudry M: Selective impairment of learning and blockade of long-term potentiation by an N-methyl-D-aspartate receptor antagonist, AP5. Nature 1986, 319:774–776.

    Article  PubMed  CAS  Google Scholar 

  5. Eichenbaum H, Harris K: Toying with memory in the hippocampus. Nat Neurosci 2000, 3:205–206.

    Article  PubMed  CAS  Google Scholar 

  6. Clayton DA, Mesches MH, Alvarez E, et al.: A hippocampal NR2B deficit can mimic age-related changes in long-term potentiation and spatial learning in the Fischer 344 rat. J Neurosci 2002, 22:3628–3637. Using antisense oligonucleotides to specifically reduce NMDA receptor NR2B subunit expression in the hippocampus of young rats, the authors demonstrate the important role of NR2B in LTP and learning and memory and suggest reduced NR2B expression may play a role in age-related cognitive decline.

    PubMed  CAS  Google Scholar 

  7. Rondi-Reig L, Libbey M, Eichenbaum H, Tonegawa S: CA1-specific N-methyl-D-aspartate receptor knockout mice are deficient in solving a nonspatial transverse patterning task. Proc Natl Acad Sci U S A 2001, 98:3543–3548.

    Article  PubMed  CAS  Google Scholar 

  8. Ball MJ: Neuronal loss, neurofibrillary tangles and granulovacuolar degeneration in the hippocampus with ageing and dementia. A quantitative study. Acta Neuropathol (Berl) 1977, 37:111–118.

    Article  CAS  Google Scholar 

  9. Hyman BT, Van Horsen GW, Damasio AR, Barnes CL: Alzheimer’s disease: cell-specific pathology isolates the hippocampal formation. Science 1984, 225:1168–1170.

    Article  PubMed  CAS  Google Scholar 

  10. Mattson MP, Kater SB: Development and selective neurodegeneration in cell cultures from different hippocampal regions. Brain Res 1989, 490:110–125.

    Article  PubMed  CAS  Google Scholar 

  11. Jansen KL, Faull RL, Dragunow M, Synek BL: Alzheimer’s disease: changes in hippocampal N-methyl-D-aspartate, quisqualate, neurotensin, adenosine, benzodiazepine, serotonin and opioid receptors—an autoradiographic study. Neuroscience 1990, 39:613–627.

    Article  PubMed  CAS  Google Scholar 

  12. Morrison JH, Hof PR: Selective vulnerability of corticocortical and hippocampal circuits in aging and Alzheimer’s disease. Prog Brain Res 2002, 136:467–486. This review differentiates between the hippocampal and neocortical pathology observed in age-related functional decline and in Alzheimer’s disease. Neuronal death predominates in Alzheimer’s disease, whereas alterations in synapse structure/morphology are associated with age-related cognitive decline.

    PubMed  CAS  Google Scholar 

  13. DeKosky ST, Scheff SW: Synapse loss in frontal cortex biopsies in Alzheimer’s disease: correlation with cognitive severity. Ann Neurol 1990, 27:457–464.

    Article  PubMed  CAS  Google Scholar 

  14. Greenamyre JT, Maragos WF, Albin RL, et al.: Glutamate transmission and toxicity in Alzheimer’s disease. Prog Neuropsychopharmacol Biol Psychiatry 1988, 12:421–430.

    Article  PubMed  CAS  Google Scholar 

  15. Rongo C: A fresh look at the role of CaMKII in hippocampal synaptic plasticity and memory. Bioessays 2002, 24:223–233. Current data on the role of CaMKII in LTP and learning and memory is reviewed.

    Article  PubMed  CAS  Google Scholar 

  16. Matias C, Dionisio JC, Quinta-Ferreira ME: Thapsigargin blocks STP and LTP related calcium enhancements in hippocampal CA1 area. Neuroreport 2002, 13:2577–2580.

    Article  PubMed  CAS  Google Scholar 

  17. Olney JW, Wozniak DF, Farber NB: Excitotoxic neurodegeneration in Alzheimer disease. New hypothesis and new therapeutic strategies. Arch Neurol 1997, 54:1234–1240.

    PubMed  CAS  Google Scholar 

  18. Doble A: The role of excitotoxicity in neurodegenerative disease: implications for therapy. Pharmacol Ther 1999, 81:163–221.

    Article  PubMed  CAS  Google Scholar 

  19. Miguel-Hidalgo JJ, Alvarez XA, Cacabelos R, Quack G:Neuroprotection by memantine against neurodegeneration induced by beta-amyloid(1-40). Brain Res 2002, 958:210–221. Preclinical data suggest that memantine, at therapeutically relevant concentrations, protects against neuronal degeneration induced by β-amyloid.

    Article  PubMed  CAS  Google Scholar 

  20. Ikegaya Y, Kim JA, Baba M, et al.: Rapid and reversible changes in dendrite morphology and synaptic efficacy following NMDA receptor activation: implication for a cellular defense against excitotoxicity. J Cell Sci 2001, 114:4083–4093.

    PubMed  CAS  Google Scholar 

  21. Penney JB, Maragos WF, Greenamyre JT, et al.: Excitatory amino acid binding sites in the hippocampal region of Alzheimer’s disease and other dementias. J Neurol Neurosurg Psychiatry 1990, 53:314–320.

    Article  PubMed  CAS  Google Scholar 

  22. Selkoe DJ: Alzheimer’s disease: genes, proteins, and therapy. Physiol Rev 2001, 81:741–766.

    PubMed  CAS  Google Scholar 

  23. Stephan A, Laroche S, Davis S: Generation of aggregated beta-amyloid in the rat hippocampus impairs synaptic transmission and plasticity and causes memory deficits. J Neurosci 2001, 21:5703–5714.

    PubMed  CAS  Google Scholar 

  24. Blessed G, Tomlinson BE, Roth M: The association between quantitative measures of dementia and of senile change in the cerebral grey matter of elderly subjects. Br J Psychiatry 1968, 114:797–811.

    Article  PubMed  CAS  Google Scholar 

  25. Gray CW, Patel AJ: Neurodegeneration mediated by glutamate and beta-amyloid peptide: a comparison and possible interaction. Brain Res 1995, 691:169–179.

    Article  PubMed  CAS  Google Scholar 

  26. Harkany T, Abraham I, Timmerman W, et al.: Beta-amyloid neurotoxicity is mediated by a glutamate-triggered excitotoxic cascade in rat nucleus basalis. Eur J Neurosci 2000, 12:2735–2745.

    Article  PubMed  CAS  Google Scholar 

  27. Arias C, Arrieta I, Tapia R: Beta-amyloid peptide fragment 25–35 potentiates the calcium-dependent release of excitatory amino acids from depolarized hippocampal slices. J Neurosci Res 1995, 41:561–566.

    Article  PubMed  CAS  Google Scholar 

  28. Koh JY, Yang LL, Cotman CW: Beta-amyloid protein increases the vulnerability of cultured cortical neurons to excitotoxic damage. Brain Res 1990, 533:315–320.

    Article  PubMed  CAS  Google Scholar 

  29. Mattson MP, Cheng B, Davis D, et al.: Beta-amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity. J Neurosci 1992, 12:376–389.

    PubMed  CAS  Google Scholar 

  30. Gotz J, Chen F, van Dorpe J, Nitsch RM: Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils. Science 2001, 293:1491–1495.

    Article  PubMed  CAS  Google Scholar 

  31. Lynch G: Memory enhancement: the search for mechanismbased drugs. Nat Neurosci 2002, 5(suppl):1035–1038. Current and comprehensive discussion on drug strategies for treatment of cognitive impairments based upon mechanisms underlying LTP.

    Article  PubMed  CAS  Google Scholar 

  32. Schuster GM, Schmidt WJ: D-cycloserine reverses the working memory impairment of hippocampal-lesioned rats in a spatial learning task. Eur J Pharmacol 1992, 224:97–98.

    Article  PubMed  CAS  Google Scholar 

  33. Jones RW, Wesnes KA, Kirby J: Effects of NMDA modulation in scopolamine dementia. Ann N Y Acad Sci 1991, 640:241–244.

    PubMed  CAS  Google Scholar 

  34. Schwartz BL, Hashtroudi S, Herting RL, et al.: d-Cycloserine enhances implicit memory in Alzheimer patients. Neurology 1996, 46:420–424.

    PubMed  CAS  Google Scholar 

  35. Tsai GE, Falk WE, Gunther J: A preliminary study of D-cycloserine treatment in Alzheimer’s disease. J Neuropsychiatry Clin Neurosci 1998, 10:224–226.

    PubMed  CAS  Google Scholar 

  36. Tsai GE, Falk WE, Gunther J, Coyle JT: Improved cognition in Alzheimer’s disease with short-term D-cycloserine treatment. Am J Psychiatry 1999, 156:467–469.

    PubMed  CAS  Google Scholar 

  37. Laake K, Oeksengaard AR: D-cycloserine for Alzheimer’s disease. Cochrane Database Syst Rev 2002, CD003153.

  38. Handelmann GE, Nevins ME, Mueller LL, et al.: Milacemide, a glycine prodrug, enhances performance of learning tasks in normal and amnestic rodents. Pharmacol Biochem Behav 1989, 34:823–828.

    Article  PubMed  CAS  Google Scholar 

  39. Semba J, Patsalos PN: Milacemide effects on the temporal inter-relationship of amino acids and monoamine metabolites in rat cerebrospinal fluid. Eur J Pharmacol 1993, 230:321–326.

    Article  PubMed  CAS  Google Scholar 

  40. Finkelstein JE, Hengemihle JM, Ingram DK, Petri HL:Milacemide treatment in mice enhances acquisition of a Morris-type water maze task. Pharmacol Biochem Behav 1994, 49:707–710.

    Article  PubMed  CAS  Google Scholar 

  41. Schwartz BL, Hashtroudi S, Herting RL, Deutsch SI: The effects of milacemide on item and source memory. Clin Neuropharmacol 1992, 15:114–119.

    Article  PubMed  CAS  Google Scholar 

  42. Dysken MW, Mendels J, LeWitt P, et al.: Milacemide: a placebocontrolled study in senile dementia of the Alzheimer type. J Am Geriatr Soc 1992, 40:503–506.

    PubMed  CAS  Google Scholar 

  43. Sveinbjornsdottir S, Sander JW, Upton D, et al.: The excitatory amino acid antagonist D-CPP-ene (SDZ EAA-494) in patients with epilepsy. Epilepsy Res 1993, 16:165–174.

    Article  PubMed  CAS  Google Scholar 

  44. Grotta J, Clark W, Coull B, et al.: Safety and tolerability of the glutamate antagonist CGS 19755 (Selfotel) in patients with acute ischemic stroke. Results of a phase IIa randomized trial. Stroke 1995, 26:602–605.

    PubMed  CAS  Google Scholar 

  45. Wenk GL, Danysz W, Mobley SL: MK-801, memantine and amantadine show neuroprotective activity in the nucleus basalis magnocellularis. Eur J Pharmacol 1995, 293:267–270.

    Article  PubMed  CAS  Google Scholar 

  46. Wenk GL, Danysz W, Mobley SL: Investigations of neurotoxicity and neuroprotection within the nucleus basalis of the rat. Brain Res 1994, 655:7–11.

    Article  PubMed  CAS  Google Scholar 

  47. Parsons CG, Danysz W, Quack G: Memantine is a clinically well tolerated N-methyl-D-aspartate (NMDA) receptor antagonist—a review of preclinical data. Neuropharmacology 1999, 38:735–767.

    Article  PubMed  CAS  Google Scholar 

  48. Kornhuber J, Weller M: Psychotogenicity and N-methyl-Daspartate receptor antagonism: implications for neuroprotective pharmacotherapy. Biol Psychiatry 1997, 41:135–144.

    Article  PubMed  CAS  Google Scholar 

  49. Rogawski MA: Low affinity channel blocking (uncompetitive) NMDA receptor antagonists as therapeutic agents—toward an understanding of their favorable tolerability. Amino Acids 2000, 19:133–149.

    Article  PubMed  CAS  Google Scholar 

  50. Jain KK: Evaluation of memantine for neuroprotection in dementia. Expert Opin Invest Drugs 2000, 9:1397–1406.

    Article  CAS  Google Scholar 

  51. Winblad B, Poritis N: Memantine in severe dementia: results of the M-Best Study (Benefit and efficacy in severely demented patients during treatment with memantine). Int J Geriatr Psychiatry 1999, 14:135–146.

    Article  PubMed  CAS  Google Scholar 

  52. Reisberg B, Doody R, Stöffler A, et al., for the Memantine Study Group: Memantine in moderate-to-severe Alzheimer’s disease. N Engl J Med 2003, 348:1333–1341. This was the first double-blind, placebo-controlled trial in the United States evaluating memantine monotherapy in patients with moderate to severe Alzheimer’s disease. At endpoint, memantine significantly improved cognitive, global, and functional outcomes compared with placebo. Memantine treatment was safe and well tolerated.

    Article  PubMed  CAS  Google Scholar 

  53. Wimo A, Winblad B, Stöffler A, et al.: Resource utilisation and cost analysis of memantine in patients with moderate to severe Alzheimer’s disease. Pharmacoeconomics 2003, 21:327–340. This analysis evaluated the effect of memantine treatment on resource utilization and costs associated with Alzheimer’s disease. Memantine treatment was associated with significantly lower caregiver time burden and a lower transition of patients to an institutional setting, as well as significantly lower caregiver and societal costs.

    Article  PubMed  CAS  Google Scholar 

  54. Reisberg B, Ferris S, Möbius HJ, et al.: Long-term treatment with the NMDA antagonist memantine: results of a 24-week open-label extension study in moderately severe-to-severe Alzheimer’s disease [abstract]. Neurobiol Aging 2002, 23:S555.

    Article  Google Scholar 

  55. Orgogozo JM, Rigaud AS, Stöffler A, et al.: Efficacy and safety of memantine in patients with mild to moderate vascular dementia: a randomized, placebo-controlled trial (MMM 300). Stroke 2002, 33:1834–1839.

    Article  PubMed  CAS  Google Scholar 

  56. Wilcock G, Möbius HJ, Stöffler A: A double-blind, placebocontrolled multicentre study of memantine in mild to moderate vascular dementia (MMM 500). Int Clin Psychopharmacol 2002, 17:297–305.

    Article  PubMed  CAS  Google Scholar 

  57. Farlow MR, Tariot PN, Grossberg GT, et al.: Memantine/donepezil dual-therapy is superior to placebo/donepezil therapy for treatment of moderate to severe Alzheimer’s disease [abstract]. Neurology 2003, 60:A412. This double-blind, placebo-controlled trial evaluated memantine therapy in patients with moderate to severe Azheimer’s disease. All patients were on stable doses of donepezil. The study demonstrated that memantine was well tolerated and resulted in significant improvement on cognitive, functional, behavioral, and global measures compared with placebo treatment.

    Google Scholar 

  58. Hartmann S, Möbius HJ: Tolerability of memantine in combination with cholinesterase inhibitors in dementia therapy. Int Clin Psychopharmacol 2003, 18:81–85. This postmarketing surveillance study of German physicians reports that memantine in combination with cholinesterase inhibitors is safe and well tolerated.

    Article  PubMed  Google Scholar 

  59. Periclou A, Ventura D, Sherman T, et al.: Pharmacokinetic study of memantine and donepezil in healthy young subjects [abstract]. J Am Med Dir Assoc 2003, 4:A1-A21.

    Google Scholar 

  60. Rammes G, Rupprecht R, Ferrari U, et al.: The N-methyl-Daspartate receptor channel blockers memantine, MRZ2/579 and other amino-alkyl-cyclohexanes antagonize 5-HT(3) receptor currents in cultured HEK-293 and N1E-115 cell systems in a non-competitive manner. Neurosci Lett 2001, 306:81–84.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Departments of Psychiatry and Medicine, and the Center for the Study of Aging, Duke University Medical Center, Box 3018, 27710, Durham, NC, USA

    P. Murali Doraiswamy MD

Authors
  1. P. Murali Doraiswamy MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Doraiswamy, P.M. The role of the N-methyl-D-aspartate receptor in Alzheimer’s disease: Therapeutic potential. Curr Neurol Neurosci Rep 3, 373–378 (2003). https://doi.org/10.1007/s11910-003-0019-8

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11910-003-0019-8

Keywords

Search

Navigation