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.
Highlights
Alzheimer’s disease is the most common form of dementia and the most prevalent neurodegenerative disease characterized by cognitive disorder and memory dysfunction in the elderly population, affecting almost 40 million people worldwide [1]
It seems that proper N-methyl-D-aspartate receptors (NMDARs) and synapse function are necessary for learning and memory, and improper of NMDAR and synapse function may participate in the pathogenesis of Alzheimer’s disease (AD) at the synaptic level
Ab-induced long-term potentiation (LTP) impairment in AD can be ameliorated by decreasing extracellular glutamate levels and inhibition of p38MAPK or calpain, which are selectively activated by extrasynaptic NMDARs [47]
Summary
Alzheimer’s disease is the most common form of dementia and the most prevalent neurodegenerative disease characterized by cognitive disorder and memory dysfunction in the elderly population, affecting almost 40 million people worldwide [1]. Ab induces glutamate release from astrocytes, which in turn activates extrasynaptic NMDARs on neurons and subsequent decrease in miniature excitatory postsynaptic currents (mEPSCs) which may reflect early synaptic injury [30]. Ab-induced LTP impairment in AD can be ameliorated by decreasing extracellular glutamate levels and inhibition of p38MAPK or calpain, which are selectively activated by extrasynaptic NMDARs [47]. Treatment of rat organotypic slices containing pyramidal neurons with Ab oligomers decrease dendritic spine density and reduce NMDAR-mediated calcium influx into active spines [50]. Overexpression of human tau in primary neuronal cultures causes cell death, which is inhibited by ifenprodil, a GluN2B selective antagonist, suggesting that tau-induced neurotoxicity by stimulation of extrasynaptic NMDARs containing GluN2B subunit. Low-frequency rTMS reverse the decreased NMDAR levels and deficits in LTP and spatial memory in Ab induced AD mouse models [68]. rTMS treatment improve the cognitive ability and language performance in AD patients suggesting that rTMS may be a effective therapeutic technique in the treatment of neurodegenerative diseases [69]
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