Regulation of NMDA receptor trafficking by amyloid-β

Abstract

Amyloid-beta peptide is elevated in the brains of patients with Alzheimer disease and is believed to be causative in the disease process. Amyloid-beta reduces glutamatergic transmission and inhibits synaptic plasticity, although the underlying mechanisms are unknown. We found that application of amyloid-beta promoted endocytosis of NMDA receptors in cortical neurons. In addition, neurons from a genetic mouse model of Alzheimer disease expressed reduced amounts of surface NMDA receptors. Reducing amyloid-beta by treating neurons with a gamma-secretase inhibitor restored surface expression of NMDA receptors. Consistent with these data, amyloid-beta application produced a rapid and persistent depression of NMDA-evoked currents in cortical neurons. Amyloid-beta-dependent endocytosis of NMDA receptors required the alpha-7 nicotinic receptor, protein phosphatase 2B (PP2B) and the tyrosine phosphatase STEP. Dephosphorylation of the NMDA receptor subunit NR2B at Tyr1472 correlated with receptor endocytosis. These data indicate a new mechanism by which amyloid-beta can cause synaptic dysfunction and contribute to Alzheimer disease pathology.

Rapid, concurrent alterations in pre- and postsynaptic structure induced by naturally-secreted amyloid-β protein

“…We found that blockade of NMDA receptors using either MK-801 or memantine attenuated the Aβ-induced changes in spine number or morphology, consistent with the idea that excess NMDA receptor activation contributes to Aβ synaptotoxicity. Furthermore, the loss and shrinkage of spines we observe is consistent with a recent study that demonstrated increased endocytosis of NMDA receptors in response to Aβ (Snyder, et al, 2005). That NMDA receptor internalization was partly dependent on activation of α7-nicotinic receptors is also consistent with our observation that a nicotinic antagonist prevented Aβ-induced changes in spine morphology.…”

Impaired AMPA signaling and cytoskeletal alterations induce early synaptic dysfunction in a mouse model of Alzheimer's disease

“…These findings are significant because post‐translational modifications regulate the incorporation of AMPARs into the synapses and also facilitate the internalization of NMDARs (Snyder et al., 2005) (Figure 2e,f). Therefore, the post‐translational modifications of AMPARs and NMDARs may be associated with the synaptic deficits observed in 3xTg‐AD mice.…”

“…Our study suggests that impairments in AMPAR activity are largely mediated by changes in AMPAR trafficking, due to reductions in multiple phosphorylation states of AMPAR subunits. The reduction in this post‐translational modification affects the incorporation of AMPARs into synapses, contributing to the associated functional deficits (Snyder et al., 2005). Taken together, our data demonstrate that synaptic AMPAR signaling is affected, leading to the early synaptic and cognitive deficits observed in this model.…”

Chronic NMDA Administration Increases Neuroinflammatory Markers in Rat Frontal Cortex: Cross-Talk Between Excitotoxicity and Neuroinflammation

“…Excitotoxicity has been implicated in the pathophysiology of various human brain disorders, including Alzheimer disease [9,10], Parkinson disease [11], Huntington disease [12], schizophrenia [13], and bipolar disorder [14][15][16]. Studies have demonstrated increased concentrations of glutamate and reduced levels of NMDA receptor (NR) subunits in the brain of some of these patients.…”