Glutamatergic dysfunctioning in Alzheimer's disease and related therapeutic targets

Dénes Zádori, Gábor Veres, Levente Szalárdy, P. Klivényi, J. Toldi, L. Vécsei

Research output: Contribution to journalArticle

49 Citations (Scopus)

Abstract

The impairment of glutamatergic neurotransmission plays an important role in the development of Alzheimer's disease (AD). The pathological process, which involves the production of amyloid-β peptides and hyperphosphorylated tau proteins, spreads over well-delineated neuroanatomical circuits. The gradual deterioration of proper synaptic functioning (via GluN2A-containing N-methyl-D-aspartate receptors, NMDARs) and the development of excitotoxicity (via GluN2B-containing NMDARs) in these structures both accompany the disease pathogenesis. Although one of the most important therapeutic targets would be glutamate excitotoxicity, the application of conventional anti-glutamatergic agents could result in further deterioration of synaptic transmission and intolerable side-effects. With regard to NMDAR antagonists with tolerable side-effects, ion channel blockers with low affinity, glycine site agents, and specific antagonists of polyamine site and GluN2B subunit may come into play. However, in the mirror of experimental data, only the application of ion channel blockers with pronounced voltage dependency, low affinity, and rapid unblocking kinetics (e.g., memantine) and specific antagonists of the GluN2B subunit (e.g., ifenprodil and certain kynurenic acid amides) resulted in desirable symptom amelioration. Therefore we propose that these kinds of chemical agents may have therapeutic potential for present and future drug development.

Original languageEnglish
Pages (from-to)S177-S187
JournalJournal of Alzheimer's Disease
Volume42
DOIs
Publication statusPublished - 2014

Fingerprint

N-Methyl-D-Aspartate Receptors
Alzheimer Disease
Ion Channels
Synaptic Transmission
Glycine Agents
Excitatory Amino Acid Agents
Kynurenic Acid
Memantine
tau Proteins
Polyamines
Pathologic Processes
Amyloid
Amides
Glutamic Acid
Therapeutics
Peptides
Pharmaceutical Preparations

Keywords

  • Alzheimer's disease
  • glutamate excitotoxicity
  • kynurenic acid amides
  • memantine
  • neurodegeneration
  • neuroprotection
  • therapy

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Geriatrics and Gerontology
  • Clinical Psychology
  • Medicine(all)

Cite this

Glutamatergic dysfunctioning in Alzheimer's disease and related therapeutic targets. / Zádori, Dénes; Veres, Gábor; Szalárdy, Levente; Klivényi, P.; Toldi, J.; Vécsei, L.

In: Journal of Alzheimer's Disease, Vol. 42, 2014, p. S177-S187.

Research output: Contribution to journalArticle

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