QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, October 12, 2005, 25(41):9367-9377; doi:10.1523/JNEUROSCI.0849-05.2005

This Article Full Text Full Text (PDF) Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (13) Citing Articles via Google Scholar Google Scholar Articles by Lesné, S. Articles by Buisson, A. Search for Related Content PubMed PubMed Citation Articles by Lesné, S. Articles by Buisson, A.

 Previous Article  |  Next Article 

Neurobiology of Disease
NMDA Receptor Activation Inhibits -Secretase and Promotes Neuronal Amyloid- Production

Sylvain Lesné,^1,3 Carine Ali,^1,2 Cecília Gabriel,¹ Nicole Croci,⁵ Eric T. MacKenzie,¹ Charles G. Glabe,⁴ Michel Plotkine,⁵ Catherine Marchand-Verrecchia,⁵ Denis Vivien,^1,2 and Alain Buisson¹

¹Unité Mixte de Recherche, Centre National de la Recherche Scientifique 6185, Centre Cyceron, and ²Equipe Institut National de la Santé et de la Recherche Médicale Avenir tPA in the Working Brain, Université de Caen, 14074 Caen Cedex, France, ³Department of Neurology, University of Minnesota, Minneapolis, Minnesota 55455, ⁴Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, California 92697, and ⁵Faculté des Sciences Pharmaceutiques et Biologiques, Université Paris 5, Laboratoire de Pharmacologie-EA2510, 75006 Paris, France

Acute brain injuries have been identified as a risk factor for developing Alzheimer's disease (AD). Because glutamate plays a pivotal role in these pathologies, we studied the influence of glutamate receptor activation on amyloid- (A) production in primary cultures of cortical neurons. We found that sublethal NMDA receptor activation increased the production and secretion of A. This effect was preceded by an increased expression of neuronal Kunitz protease inhibitory domain (KPI) containing amyloid- precursor protein (KPI-APP) followed by a shift from -secretase to -secretase-mediated APP processing. This shift is a result of the inhibition of the -secretase candidate tumor necrosis factor- converting enzyme (TACE) when associated with neuronal KPI-APPs. This KPI-APP/TACE interaction was also present in AD brains. Thus, our findings reveal a cellular mechanism linking NMDA receptor activation to neuronal A secretion. These results suggest that even mild deregulation of the glutamatergic neurotransmission may increase A production and represent a causal risk factor for developing AD.

Key words: amyloid; APP; secretase; glutamate receptors; calmodulin; neurons

---

Received March 3, 2005; revised July 8, 2005; accepted August 29, 2005.

This article has been cited by other articles:

				C. L. Masters and K. Beyreuther Alzheimer's centennial legacy: prospects for rational therapeutic intervention targeting the A{beta} amyloid pathway Brain, November 1, 2006; 129(11): 2823 - 2839. [Abstract] [Full Text] [PDF]

				H. A. Pearson and C. Peers Physiological roles for amyloid {beta} peptides J. Physiol., August 15, 2006; 575(1): 5 - 10. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help