Differential Regulation of N-Methyl-D-Aspartate Receptor Subunits is an Early Event in the Actions of Soluble Amyloid-β(1-40) Oligomers on Hippocampal Neurons.

Abstract

Synaptic dysfunction during early stages of Alzheimer's disease (AD) is triggered by soluble amyloid-β (Aβ) oligomers that interact with NMDA receptors (NMDARs). We previously showed that Aβ induces synaptic protein loss through NMDARs, albeit through undefined mechanisms. Accordingly, we here examined the contribution of individual NMDAR subunits to synaptotoxicity and demonstrate that Aβ exerts differential effects on the levels and distribution of GluN2A and GluN2B subunits of NMDAR in dendrites. Treatment of cultured hippocampal neurons with Aβ1-40 (10 μM, 1 h) induced a significant increase of dendritic and synaptic GluN2B puncta densities with parallel decreases in the puncta densities of denritic and synaptic pTyr1472-GluN2B. Conversely, Aβ significantly decreased dendritic and synaptic GluN2A and dendritic pTyr1325-GluN2A puncta densities and increased synaptic pTyr1325-GluN2A puncta densities. Unexpectedly, Aβ treatment resulted in a significant reduction of GluN2B and pTyr1472-GluN2B protein levels but did not influence GluN2A and pTyr1325-GluN2A levels. These results show that Aβ exerts complex and distinct regulatory effects on the trafficking and phosphorylation of GluN2A and GluN2B, as well as on their localization within synaptic and non-synaptic sites. Increased understanding of these early events in Aβ-induced synaptic dysfunction is likely to be important for the development of timely preventive and therapeutic interventions.

• Authors: Lirong Chang, Yali Zhang, Jinping Liu, Yizhi Song, Angchu Lv, Yan Li, Wei Zhou, Zhen Yan, Osborne F X Almeida, Yan Wu
• Journal: Journal of Alzheimer's disease : JAD (J Alzheimers Dis) Vol. 51 Issue 1 Pg. 197-212 ( 2016) ISSN: 1875-8908 [Electronic] Netherlands
• PMID: 26836185 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid beta-Peptides
• NR2B NMDA receptor
• Peptide Fragments
• Receptors, N-Methyl-D-Aspartate
• amyloid beta-protein (1-40)
• N-methyl D-aspartate receptor subtype 2A

Topics

• Amyloid beta-Peptides (pharmacology)
• Animals
• Animals, Newborn
• Cells, Cultured
• Dendrites (drug effects, metabolism)
• Gene Expression Regulation (drug effects)
• Hippocampus (cytology)
• Male
• Neurons (cytology, drug effects)
• Peptide Fragments (pharmacology)
• Phosphorylation (drug effects)
• Rats
• Rats, Wistar
• Receptors, N-Methyl-D-Aspartate (metabolism)