Aberrant expression of metabotropic glutamate receptor 2 in the vulnerable neurons of Alzheimer's disease

Hyoung Gon Lee, Osamu Ogawa, Xiongwei Zhu, Michael J. O'Neil, Robert B. Petersen, Rudolph J. Castellani, Hossein Ghanbari, George Perry, Mark A. Smith

Research output: Contribution to journalArticlepeer-review

52 Scopus citations

Abstract

Selective neuronal dysfunction and degeneration are defining features of Alzheimer's disease (AD). While the exact mechanism(s) contributing to this selective neuronal vulnerability remains to be elucidated, we hypothesized that the differential expression of metabotropic glutamate receptors (mGluRs) may play a key role in this process since the various mGluR groups differentially regulate neuronal cell death and survival. In the present study, we focused on the metabotropic glutamate receptor 2 (mGluR2), a subtype of group II mGluRs. The mGluR2 is expressed at low levels in pyramidal neurons in age-matched control cases, whereas we found a strikingly increased mGluR2 expression in AD, in a pattern that mirrored both the regional and cellular subtype of neuronal vulnerability to degeneration and neurofibrillary alterations. Immunoblot analysis confirmed the significant increase in the level of mGluR2 in AD compared with age-matched controls. Agonists for group II mGluRs activate extracellular receptor kinase (ERK), a kinase that is chronically activated in vulnerable neurons of AD. ERK is able to phosphorylate tau protein, so the up-regulation of mGluR2 in vulnerable neurons may represent the upstream mediator of abnormal tau phosphorylation in AD. Immunocytochemical examination revealed considerable overlap between mGluR2 and neurofibrillary alterations. Thus, it is likely that mGluR2 represents a novel therapeutic target for AD.

Original languageEnglish
Pages (from-to)365-371
Number of pages7
JournalActa Neuropathologica
Volume107
Issue number4
DOIs
StatePublished - Apr 2004

Keywords

  • Alzheimer's disease
  • Glutamate
  • Metabotropic glutamate receptor
  • Neurofibrillary pathology

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