NMDA and AMPA Receptors Dysregulation in Alzheimer's Disease

Alzheimer's disease (AD) is a progressive neurodegenerative condition characterized by cognitive dysfunction and synaptic failure. The current therapeutic approaches are mainly focused on symptomatic treatment and possess limited effectiveness in addressing the pathophysiology of AD. It is known that neurodegeneration is negatively correlated with synaptic plasticity. This negative correlation highlights glutamatergic neurotransmission via N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors and (AMPA) receptors as a critical mediator of synaptic plasticity. Despite this favorable role, extensive extracellular glutamate concentration induces excitotoxicity and neurodegeneration. NMDA receptors containing GluN2A subunits are located at synaptic sites, implicated in the protective pathways. In comparison, GluN2B containing receptors are located mainly at extrasynaptic sites and increase neuronal vulnerability. AMPA receptors are consistently endocytosed and recycled back to the membrane. An increase in the rate of endocytosis has been implicated as a part of AD pathophysiology through inducing long-term depression (LTD) and synaptic disintegration. In the present review, we focused on the mechanisms of glutamatergic system dysregulation in AD, particularly on its interaction with amyloid-beta. We concluded that assigning a specific role to an individual subtype of either NMDA receptors or AMPA receptors might be an oversimplification as they are not static receptors. Therefore, any imbalance between synaptic and extrasynaptic NMDA receptors and a reduced number of surface AMPA receptors will lead to synaptopathy.