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

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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

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

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