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

• Published in: Alzheimer's & dementia Vol. 20; no. 12; pp. 8231 - 8245
• Main Authors: Escamilla, Sergio, Badillos, Raquel, Comella, Joan X., Solé, Montse, Pérez‐Otaño, Isabel, Mut, Jose V. Sánchez, Sáez‐Valero, Javier, Cuchillo‐Ibáñez, Inmaculada
• Format: Journal Article
• Language: English
• Published: United States John Wiley and Sons Inc 01.12.2024
• Subjects: Aged; Aged, 80 and over; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer´s disease; Cerebral Cortex - metabolism; extrasynaptic; Female; Frontal Lobe - metabolism; GluN1; GluN2A; GluN2B; GluN3A; human; Humans; Male; Middle Aged; NMDA; Phosphorylation; Protein Processing, Post-Translational; Receptors, N-Methyl-D-Aspartate - metabolism; Synapses - metabolism; Tyr1336; Tyr1472; Tyr1336; Alzheimer´s disease; extrasynaptic; GluN1; NMDA; Tyr1472; GluN3A; GluN2A; human; GluN2B
• ISSN: 1552-5260; 1552-5279; 1552-5279
• DOI: 10.1002/alz.14125

BACKGROUND 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. METHODS 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. RESULTS 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. DISCUSSION 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. Highlights New protocol to isolate synaptic and extrasynaptic membranes from the human cortex. Low GluN2B and GluN2A levels in Alzheimer´s disease (AD) synaptic membranes. High GluN2B and GluN1 levels in AD extrasynaptic membranes. Specific glycoforms of extrasynaptic GluN2B and GluN2A. Low phosphorylation at Tyr1472 in synaptic GluN2B in AD.