Dementia Japan 31:94-116, 2017

Alzheimer's disease and N-Methyl-D-aspartate (NMDA) receptors:extrasynaptic NMDA receptor hypothesis

Yasumasa Yoshiyama^1,3), Yu Nakamura²⁾

¹⁾Inage Neurology and Memory Clinic
²⁾Department Psychiatry and Neurology, Kagawa University Faculty of Medicine/Graduate School of Medicine
³⁾Department of Neurology, Chiba-East National Hospital

N-Methyl-D-Aspartate receptor (NMDAR) plays an important role in memory and learning.  In Alzheimer's disease (AD) its function is disrupted by elevated glutamate concentration.  Recently, it was shown that NMDARs are located at synaptic sites (synaptic NMDAR, sNMDAR) and extrasynaptic sites (extrasynaptic NMDAR, eNMDAR), with each having different functions.  Activation of sNMDAR induces neuronal plasticity and neuroprotective effects;whereas in AD, activation of eNMDAR stimulated by spillover glutamate from synapses induces continuous tonic current and neurotoxic effects with excess Ca²⁺ influx.  Interestingly, experiments using cell culture systems have demonstrated that Aβ oligomers reduce sNMDAR and increase eNMDAR.  Activation of eNMDAR with Aβ oligomers was shown to concomitantly increase production of Aβ and increase phosphorylation of tau protein, both of which are believed to accelerate AD pathologies.  These findings indicate that the pathological activation of eNMDAR in AD might be a crucial mechanism involved in both Aβ and tau pathologies.  Memantine is an NMDAR antagonist used for treatment of moderate to severe AD;however, recently it was reported that it has a selective inhibitory effect on eNMDAR, thus leading to reconsideration of its underlying mechanism and significance as treatment for AD.

Address correspondence to Dr. Yasumasa Yoshiyama, Inage Neurology and Memory Clinic (6-23-9 Konakadai, Inage-ku, Chiba, Chiba Prefecture 263-0043, Japan)