Dysfunction of NMDA receptors in Alzheimer's disease

Abstract

N-methyl-D-aspartate receptors (NMDARs) play a pivotal role in the synaptic transmission and synaptic plasticity thought to underlie learning and memory. NMDARs activation has been recently implicated in Alzheimer's disease (AD) related to synaptic dysfunction. Synaptic NMDARs are neuroprotective, whereas overactivation of NMDARs located outside of the synapse cause loss of mitochondrial membrane potential and cell death. NMDARs dysfunction in the glutamatergic tripartite synapse, comprising presynaptic and postsynaptic neurons and glial cells, is directly involved in AD. This review discusses that both beta-amyloid (Aβ) and tau perturb synaptic functioning of the tripartite synapse, including alterations in glutamate release, astrocytic uptake, and receptor signaling. Particular emphasis is given to the role of NMDARs as a possible convergence point for Aβ and tau toxicity and possible reversible stages of the AD through preventive and/or disease-modifying therapeutic strategies.

Keywords: AD; Extrasynaptic; NMDA receptors; Synaptic transmission; Tripartite synapse.

Fig. 1

Structure and domain organization of NMDA receptors. Linear representation of the subunit polypeptide chain and schematic illustration of the subunit topology. NMDARs subunits have a modular structure composed of two extracellular domains [the ATD (green) and the LBD (yellow)]; a TMD (cyan) that forms part of the ion channel pore; and an intracellular CTD. The LBD is defined by two segments of amino acids termed S1 and S2. The TMD contains three membrane-spanning helices (M1, M3, and M4) and a membrane re-entrant loop (M2)

Fig. 2

The tripartite glutamate synapse. Neurotransmitter molecules sequester in vesicles of the presynaptic neuron, glutamate is released into the synaptic cleft. Once released, glutamate bind to and activate a variety of ionotropic and metabotropic receptors on postsynaptic and presynaptic neurons as well as glial cells. The activation of NMDARs localized in the postsynaptic membrane leading to Ca²⁺ entry through the NMDARs and the propagation of the action potential. Glutamate can then be taken up by surrounding astrocytes through EAAT1/2 or by the presynaptic terminal through EAAT2/5, and then stored into vesicles. The activation can also be modulated by glycine released from neurons and astrocytes or d-serine released by astrocytes. Both glycine and d-serine can also be taken up by the presynaptic terminal or astrocytes by their respective transporters