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

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