Amyloid β/PKC-dependent alterations in NMDA receptor composition are detected in early stages of Alzheimer′s disease

Amyloid beta (A beta)-mediated synapse dysfunction is an early event in Alzheimer's disease (AD) pathogenesis and previous studies suggest that NMDA receptor (NMDAR) dysregulation may contribute to these pathological effects. Although A beta peptides impair NMDAR expression and activity, the mechanisms mediating these alterations in the early stages of AD are unclear. Here, we observed that NMDAR subunit NR2B and PSD-95 levels were aberrantly upregulated and correlated with A beta(42) load in human postsynaptic fractions of the prefrontal cortex in early stages of AD patients, as well as in the hippocampus of 3xTg-AD mice. Importantly, NR2B and PSD95 dysregulation was revealed by an increased expression of both proteins in A beta-injected mouse hippocampi. In cultured neurons, A beta oligomers increased the NR2B-containing NMDAR density in neuronal membranes and the NMDA-induced intracellular Ca2+ increase, in addition to colocalization in dendrites of NR2B subunit and PSD95. Mechanistically, A beta oligomers required integrin beta 1 to promote synaptic location and function of NR2B-containing NMDARs and PSD95 by phosphorylation through classic PKCs. These results provide evidence that A beta oligomers modify the contribution of NR2B to NMDAR composition and function in the early stages of AD through an integrin beta 1 and PKC-dependent pathway. These data reveal a novel role of A beta oligomers in synaptic dysfunction that may be relevant to early-stage AD pathogenesis.

Automated summary

Research has shown that Aβ oligomers play a novel role in synaptic dysfunction in the early stages of Alzheimer's disease by modifying the contribution of NR2B to NMDAR composition and function through an integrin β1 and PKC-dependent pathway.