NMDA receptor activation inhibits α-secretase and promotes neuronal amyloid-β production

Sylvain Lesné, Carine Ali, Cecília Gabriel, Nicole Croci, Eric T. MacKenzie, Charles G. Glabe, Michel Plotkine, Catherine Marchand-Verrecchia, Denis Vivien, Alain Buisson

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161 Scopus citations


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-β (Aβ) production in primary cultures of cortical neurons. We found that sublethal NMDA receptor activation increased the production and secretion of Aβ. This effect was preceded by an increased expression of neuronal Kunitz protease inhibitory domain (KPI) containing amyloid-β precursor protein (KPI-APP) followed by a shift from α-secretase to β-secretase-mediated APP processing. This shift is a result of the inhibition of the α-secretase candidate tumor necrosis factor-α 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 Aβ secretion. These results suggest that even mild deregulation of the glutamatergic neurotransmission may increase Aβ production and represent a causal risk factor for developing AD.

Original languageEnglish (US)
Pages (from-to)9367-9377
Number of pages11
JournalJournal of Neuroscience
Issue number41
StatePublished - Oct 12 2005


  • APP
  • Amyloid
  • Calmodulin
  • Glutamate receptors
  • Neurons
  • Secretase


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