Role of Glutamate and NMDA Receptors in Alzheimer's Disease

Abstract

Excitatory glutamatergic neurotransmission via N-methyl-d-aspartate receptor (NMDAR) is critical for synaptic plasticity and survival of neurons. However, excessive NMDAR activity causes excitotoxicity and promotes cell death, underlying a potential mechanism of neurodegeneration occurred in Alzheimer's disease (AD). Studies indicate that the distinct outcomes of NMDAR-mediated responses are induced by regionalized receptor activities, followed by different downstream signaling pathways. The activation of synaptic NMDARs initiates plasticity and stimulates cell survival. In contrast, the activation of extrasynaptic NMDARs promotes cell death and thus contributes to the etiology of AD, which can be blocked by an AD drug, memantine, an NMDAR antagonist that selectively blocks the function of extrasynaptic NMDARs.

Keywords: Alzheimer’s disease; NMDA receptors; excitotoxicity; extrasynaptic NMDA receptors; glutamate; memantine.

Figure 1

The association of Alzheimer’s disease with Aβ, phosphorylated tau, mitochondria dysfunction and neuronal degeneration. Amyloid plaques and neurofibrillary tangles are commonly seen pathological changes in AD, which are formed from Aβ and phosphorylated tau, respectively. Aβ and amyloid plaques triggers oxidative stress and mitochondrial dysfunction, which damages synapses and promotes neuron degeneration. Neurofibrillary tangles aggravates these processes. The significant synaptic loss and neuronal death manifests the symptoms of Alzheimer’s disease.

Figure 2

Activation of synaptic NMDAR mediates survival pathway and induces LTP and LTD. In classical synaptic plasticity model, synaptic NMDAR activity activates CaMKII and phosphatases, which triggers LTP and LTD, respectively. Moreover, the activation of synaptic NMDARs suppresses the pro-apoptotic signaling molecules and pathways such as caspases, APAF1 and Puma occurred in cytoplasm; and it also promotes the expression of the pro-survival transcriptional factors such as CREB and suppresses the expression of pro-apoptotic transcription factors such as FOXO and p53, which, in turn, inhibits apoptosis and promotes cell survival.

Figure 3

Regionalized NMDAR activity determines cell fate. In principle, extrasynaptic NMDAR-mediated apoptosis antagonizes synaptic NMDAR-mediated survival. In Alzheimer’s disease, glutamate released from astrocytes activates extrasynaptic NMDARs and triggers pro-apoptotic signaling (red) that overcomes synaptic NMDAR-mediated survival signaling (green) that is already undermined by other mechanisms such as the endocytosis of NMDARs, leading to further synaptic damage and eventual neuronal death.