title: 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.affiliation: Department of Anatomy, Ministry of Science and Technology Laboratory of Brain Disorders, Beijing Institute for Brain Disorders, Capital Medical University, Beijing, China.
authors.forename: Lirong
authors.initials: L
authors.lastname: Chang
authors.affiliation: Department of Anatomy, Ministry of Science and Technology Laboratory of Brain Disorders, Beijing Institute for Brain Disorders, Capital Medical University, Beijing, China.
authors.forename: Yali
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: School of Medicine, Tsinghua University, Beijing, China.
authors.forename: Jinping
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Anatomy, Ministry of Science and Technology Laboratory of Brain Disorders, Beijing Institute for Brain Disorders, Capital Medical University, Beijing, China.
authors.forename: Yizhi
authors.initials: Y
authors.lastname: Song
authors.affiliation: Department of Anatomy, Ministry of Science and Technology Laboratory of Brain Disorders, Beijing Institute for Brain Disorders, Capital Medical University, Beijing, China.
authors.forename: Angchu
authors.initials: A
authors.lastname: Lv
authors.affiliation: Department of Anatomy, Ministry of Science and Technology Laboratory of Brain Disorders, Beijing Institute for Brain Disorders, Capital Medical University, Beijing, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Anatomy, Ministry of Science and Technology Laboratory of Brain Disorders, Beijing Institute for Brain Disorders, Capital Medical University, Beijing, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Department of Anatomy, Ministry of Science and Technology Laboratory of Brain Disorders, Beijing Institute for Brain Disorders, Capital Medical University, Beijing, China.|Department of Physiology and Biophysics, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Buffalo, NY, USA.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Yan
authors.affiliation: Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Osborne F X
authors.initials: OF
authors.lastname: Almeida
authors.affiliation: Department of Anatomy, Ministry of Science and Technology Laboratory of Brain Disorders, Beijing Institute for Brain Disorders, Capital Medical University, Beijing, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wu
mesh_terms: D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D003712:Dendrites / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D006624:Hippocampus / Q000166:cytology*; D008297:Male; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D010446:Peptide Fragments / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D016194:Receptors, N-Methyl-D-Aspartate; C121001:NR2B NMDA receptor; C078592:amyloid beta-protein (1-40)
keywords: Alzheimer’s disease; NMDA receptor subunits; amyloid beta; hippocampus; synapse; tyrosine phosphorylation