The NMDA Receptor Hypothesis in Alzheimer’s Disease Unraveling the Mechanisms

NMDA-dependent excitatory glutamatergic neurotransmission is essential for neuroprotection, neuronal survival, and synaptic plasticity, which are thought to underlie core memory and learning processes. Studies suggest that various implications of NMDAR-mediated responses are driven by regionalized receptor expression, followed by multiple downstream signaling pathways. The overactivation of NMDARs positioned in extrasynaptic regions causes mitochondrial membrane potential loss, excitotoxicity, and cell death. Tau proteins and Aβ significantly impair the synaptic activity of the tripartite synapse in Alzheimer's disease (AD), involving variations in astrocytic uptake, glutamate release, and receptor signaling. Early synaptic dysregulation is linked to elevated oligomeric Aβ peptide, which induces NMDAR-dependent synaptic loss, depression, and spine ablation. There is currently a lack of convincing data establishing the underlying molecular processes and the link between NMDAR dysfunction and AD. AD treatment using an NMDAR antagonist began a few decades ago with limited results. Memantine, a low-affinity blocker of the NMDAR channel, has been used to treat moderate to severe AD. This chapter will emphasize the expression of NMDARs concerning AD, as well as provide information on current breakthroughs in the inhibitor discovery pipeline.