Synaptic and extrasynaptic distribution of NMDA receptors in the cortex of Alzheimer's disease patients

Synaptic and extrasynaptic distribution of N-methyl-D-aspartate receptors (NMDARs) has not been addressed in the brain from Alzheimer's disease (AD) subjects, despite their contribution to neurodegeneration. We have developed a protocol to isolate synaptic and extrasynaptic membranes from contr...

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Bibliographic Details
Authors: Escamilla, Sergio, Badillos Rodríguez, Raquel|||0000-0002-8257-1784, Comella i Carnicé, Joan Xavier|||0000-0002-6218-0786, Solé Piñol, Montserrat|||0000-0003-4240-6562, Pérez-Otaño, Isabel, Sánchez-Mut, José Vicente|||0000-0002-9292-8521, Sáez-Valero, Javier, Cuchillo-Ibáñez, Inmaculada|||0000-0002-3689-5518
Format: article
Publication Date:2024
Country:España
Institution:Universitat Autònoma de Barcelona
Repository:Dipòsit Digital de Documents de la UAB
Language:English
OAI Identifier:oai:ddd.uab.cat:305693
Online Access:https://ddd.uab.cat/record/305693
https://dx.doi.org/urn:doi:10.1002/alz.14125
Access Level:Open access
Keyword:Alzheimer's disease
Extrasynaptic
GluN1
GluN2A
GluN2B
GluN3A
Human
NMDA
Tyr1336
Tyr1472
Description
Summary:Synaptic and extrasynaptic distribution of N-methyl-D-aspartate receptors (NMDARs) has not been addressed in the brain from Alzheimer's disease (AD) subjects, despite their contribution to neurodegeneration. We have developed a protocol to isolate synaptic and extrasynaptic membranes from controls and AD frontal cortex. We characterized the distribution of the NMDAR subunits GluN2B, GluN2A, GluN1, and GluN3A, as well as post-translational modifications, such as phosphorylation and glycosylation. Lower levels of synaptic GluN2B and GluN2A were found in AD fractions, while extrasynaptic GluN2B and GluN1 levels were significantly higher; GluN3A distribution remained unaffected in AD. We also identified different glycoforms of GluN2B and GluN2A in extrasynaptic membranes. Synaptic Tyr1472 GluN2B phosphorylation was significantly lower in AD fractions. Reduction of synaptic NMDAR subunits, particularly for GluN2B, is likely to contribute to synaptic transmission failure in AD. Additionally, the increment of extrasynaptic NMDAR subunits could favor the activation of excitotoxicity in AD.

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