Activation of Extrasynaptic, But Not Synaptic, NMDA Receptors Modifies Amyloid Precursor Protein Expression Pattern and Increases Amyloid-β Production

Abstract

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 ␤-amyloid (A␤), and contributing to the initiation of Alzheimer's disease (AD). A linkage between excessive glutamate receptor activation and neuronal A␤ 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 A␤. 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 A␤ 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 A␤ release. Altogether, these data suggest that a chronic activation of extrasynaptic NMDAR promotes amyloidogenic KPI-APP expression leading to neuronal A␤ release, representing a causal risk factor for developing AD.

Aβ induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss

“…Although this paradigm first was demonstrated for ischemic brain disease, accumulating evidence suggests that it also is true for neurodegenerative disorders involving protein misfolding, such as Huntington disease (3,4) and AD (7,8,59,60). Additionally, linking this dichotomy of eNMDAR vs. sNMDAR activation to synaptic integrity, we and others previously have shown that low levels of glutamate or endogenous synaptic activity may enhance dendritic spine growth (61,62).…”

Synapses, NMDA receptor activity and neuronal Aβ production in Alzheimer’s disease

“…In the same way, this dichotomous nature of NMDAR signaling has also been outlined in the fi eld of neurological disorders (Hardingham and Bading , 2010 ). Recently, our group provided data suggesting that perturbations in the balance between synaptic and extrasynaptic NMDAR activity could increase neuronal A β production, contributing to the pathogenesis of AD (Bordji et al , 2010 ).…”

“…In a recent study, we have evidenced a direct relationship between prolonged extrasynaptic NMDAR activation and neuronal A β production (Bordji et al , 2010 ). The release of A β was preceded by the neuronal induction of KPI-APPs, isoforms exhibiting an important amyloidogenic potential.…”

“…Thus, we recently studied the infl uence of a selective stimulation of both populations of receptors on APP metabolism and A β production (Bordji et al , 2010 ). In primary cultures of cortical neurons, prolonged stimulation of extrasynaptic, but not synaptic, NMDARs importantly increased the neuronal production of A β .…”

Convergent pathogenic pathways in Alzheimer's and Huntington's diseases: shared targets for drug development

“…In mouse models of AD and HD, neurons derived from affected brain regions have defective LTP 25,26 . Furthermore, the activation of extrasynaptic NMDARs in a mouse model of AD promotes ß-secretase cleavage of APP, which results in increased levels of Aβ that are directly correlated with the severity of the cognitive deficit 27 . The presence of Aβ oligomers, early intermediates in the Aβ aggregation pathway, has in turn been associated with increased activation of extrasynaptic NMDARs, which could cause a feedback loop leading to synaptic dysfunction 28 .…”