Synaptic vs Extrasynaptic NMDA receptors distribution in Alzheimer’s human brain

Abstract

AbstractBackgroundThe malfunction of NMDA receptors (NMDARs) is believed to play a key role in Alzheimer’s Disease (AD), the most prevalent type of dementia. NMDARs are activated in different ways: activation at synapses leads to synaptic plasticity, while activation outside of synapses causes excitotoxicity, harm to mitochondria, and cell death. The objective of our research is to better understand the distribution of NMDARs in the brain of individuals with AD, specifically focusing on the distinction between synaptically and extrasynaptically activated NMDARs.MethodOur research involved separating the synaptic and extrasynaptic membranes from the frontal cortex of both Alzheimer’s Disease (AD) patients and individuals without dementia. We examined the quantity of NMDAR subunits GluN1, GluN2B, and GluN2A. Additionally, we investigated the phosphorylation of GluN2B at Y1472 and Y1336, which are linked to synaptic and extrasynaptic membranes, respectively. To achieve our goal, we employed two distinct mouse models of AD: TAUP301S and APPswe/PS1dE9.ResultOur findings revealed that in comparison to non‐demented individuals, the levels of GluN1, GluN2B, GluN2A, and pY1472‐GluN2B at synaptic membranes were lower in Alzheimer’s Disease (AD) patients. At extrasynaptic membranes, we observed an elevation in GluN2B levels and a decline in Y1336‐GluN2B phosphorylation. We also found that the changes in GluN2B phosphorylation were consistent with the APPswe/PS1dE9 mouse models of AD.ConclusionOur research discovered that levels of GluN1, GluN2B, GluN2A, and pY1472‐GluN2B were decreased at the synaptic membranes of Alzheimer’s Disease patients compared to individuals without dementia. Additionally, an increase of GluN2B levels and a decrease in Y1336‐GluN2B phosphorylation were seen at extrasynaptic membranes. Furthermore, the alterations in GluN2B phosphorylation were also mirrored in the APPswe/PS1dE9 mouse models for AD.