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

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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.

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Acknowledgement

This work was supported by funding from the Alzheimer Association and the National Institute of Health.

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Authors and Affiliations

  1. Institute of Pathology, Case Western Reserve University, 2085 Adelbert Road, Cleveland, OH, 44106, USA

    Hyoung-gon Lee, Osamu Ogawa, Xiongwei Zhu, Robert B. Petersen, Rudolph J. Castellani, George Perry & Mark A. Smith

  2. Eli Lilly & Co. Ltd., Lilly Research Centre, Windlesham, Surrey, UK

    Michael J. O’Neill

  3. Panacea Pharmaceuticals, Rockville, MD, 20850, USA

    Hossein Ghanbari

Authors
  1. Hyoung-gon Lee
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  2. Osamu Ogawa
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  3. Xiongwei Zhu
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  4. Michael J. O’Neill
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  5. Robert B. Petersen
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  6. Rudolph J. Castellani
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  7. Hossein Ghanbari
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  8. George Perry
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  9. Mark A. Smith
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Correspondence to Mark A. Smith.

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Lee, Hg., Ogawa, O., Zhu, X. et al. Aberrant expression of metabotropic glutamate receptor 2 in the vulnerable neurons of Alzheimer’s disease. Acta Neuropathol 107, 365–371 (2004). https://doi.org/10.1007/s00401-004-0820-8

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  • DOI: https://doi.org/10.1007/s00401-004-0820-8

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