Affiliations: [a] Department of Anatomy, Ministry of Science and Technology Laboratory of Brain Disorders, Beijing Institute for Brain Disorders, Capital Medical University, Beijing, China | [b] Departments of Neurology and Anatomy, University of Ulm School of Medicine, Germany | [c] Max Planck Institute of Psychiatry, Munich, Germany | [d] School of Medicine, Tsinghua University, Beijing, China
Correspondence:
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Correspondence to: Yan Wu, Department of Anatomy, Beijing Institute for Brain Disorders, Capital Medical University, Beijing, China. Tel.: +86 10 83911818; Fax: +86 10 83911452; E-mail: [email protected].
Note: [1] These authors contributed equally to this work.
Abstract: Early-stage Alzheimer’s disease (AD) is characterized by synaptic dysfunction, a phenomenon in which soluble oligomers of amyloid-beta (Aβ) and N-methyl-D-aspartate receptor (NMDAR) are implicated. Here, we demonstrated that astrocytes express NMDARs and therefore have the potential to modulate the synaptotoxic actions of Aβ. We found that specific pharmacological antagonism of two of the major NMDAR subunits, GluN2A and GluN2B, exacerbates Aβ-induced synaptotoxicity suggesting, for the first time, that astrocytic GluN2A and GluN2B mediate synaptoprotection. From the perspective of the pathogenic mechanisms of Alzheimer’s disease, in which Aβ and NMDAR play significant roles, these observations are striking since neuronal GluN2A and GluN2B are well known modulators of neurodegeneration. We did initial studies to understand the basis for the differential effects of astrocytic and neuronal GluN2A and GluN2B in the promotion of synapse survival, and identified a neurotrophin produced by astrocytes, nerve growth factor β (β-NGF), as a likely mediator of the synaptoprotective effects of astrocytic GluN2A and GluN2B activation. The results presented suggest that astrocytes may be suitable druggable targets for the prevention and/or delay of the synaptic loss that occurs during early stages of AD.
