Activation of extrasynaptic, but not synaptic, NMDA receptors modifies amyloid precursor protein expression pattern and increases amyloid-β production
Journal of Neuroscience. 2010-11-24; 30(47): 15927-15942
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1. J Neurosci. 2010 Nov 24;30(47):15927-42. doi: 10.1523/JNEUROSCI.3021-10.2010.
Activation of extrasynaptic, but not synaptic, NMDA receptors modifies amyloid
precursor protein expression pattern and increases amyloid-ß production.
Bordji K(1), Becerril-Ortega J, Nicole O, Buisson A.
(1)Unité Mixte de Recherche, Centre National de la Recherche Scientifique, Caen,
Calcium is a key mediator controlling essential neuronal functions depending on
electrical activity. Altered neuronal calcium homeostasis affects metabolism of
amyloid precursor protein (APP), leading to increased production of β-amyloid
(Aβ), and contributing to the initiation of Alzheimer’s disease (AD). A linkage
between excessive glutamate receptor activation and neuronal Aβ release was
established, and recent reports suggest that synaptic and extrasynaptic NMDA
receptor (NMDAR) activation may have distinct consequences in plasticity, gene
regulation, and neuronal death. Here, we report for the first time that prolonged
activation of extrasynaptic NMDAR, but not synaptic NMDAR, dramatically increased
the neuronal production of Aβ. This effect was preceded by a shift from APP695 to
Kunitz protease inhibitory domain (KPI) containing APPs (KPI-APPs), isoforms
exhibiting an important amyloidogenic potential. Conversely, after synaptic NMDAR
activation, we failed to detect any KPI-APP expression and neuronal Aβ production
was not modified. Calcium imaging data showed that intracellular calcium
concentration after extrasynaptic NMDAR stimulation was lower than after synaptic
activation. This suggests distinct signaling pathways for each pool of receptors.
We found that modification of neuronal APP expression pattern triggered by
extrasynaptic NMDAR activation was regulated at an alternative splicing level
involving calcium-/calmodulin-dependent protein kinase IV, but overall APP
expression remained identical. Finally, memantine dose-dependently inhibited
extrasynaptic NMDAR-induced KPI-APPs expression as well as neuronal Aβ release.
Altogether, these data suggest that a chronic activation of extrasynaptic NMDAR
promotes amyloidogenic KPI-APP expression leading to neuronal Aβ release,
representing a causal risk factor for developing AD.
PMID: 21106831 [Indexed for MEDLINE]