Role of Excitatory Amino Acid Transporter‐2 (EAAT2) and glutamate in neurodegeneration: Opportunities for developing novel therapeutics

Abstract

Glutamate is an essential excitatory neurotransmitter regulating brain functions. Excitatory amino acid transporter (EAAT)-2 is one of the major glutamate transporters expressed predominantly in astroglial cells and is responsible for 90% of total glutamate uptake. Glutamate transporters tightly regulate glutamate concentration in the synaptic cleft. Dysfunction of EAAT2 and accumulation of excessive extracellular glutamate has been implicated in the development of several neurodegenerative diseases including Alzheimer’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. Analysis of the 2.5-kb human EAAT2 promoter showed that NF-κB is an important regulator of EAAT2 expression in astrocytes. Screening of approximately 1,040 FDA-approved compounds and nutritionals led to the discovery that many β-lactam antibiotics are transcriptional activators of EAAT2 resulting in increased EAAT2 protein levels. Treatment of animals with ceftriaxone (CEF), a β-lactam antibiotic, led to an increase of EAAT2 expression and glutamate transport activity in the brain. CEF has neuroprotective effects in both in vitro and in vivo models based on its ability to inhibit neuronal cell death by preventing glutamate excitotoxicity. CEF increases EAAT2 transcription in primary human fetal astrocytes (PHFA) through the NF-κB signaling pathway. The NF-κB binding site at −272 position was critical in CEF-mediated EAAT2 protein induction. These studies emphasize the importance of transcriptional regulation in controlling glutamate levels in the brain. They also emphasize the potential utility of the EAAT2 promoter for developing both low and high throughput screening assays to identify novel small molecule regulators of glutamate transport with potential to ameliorate pathological changes occurring during and causing neurodegeneration.

Astrocytic transporters in Alzheimer's disease

“…It is also noteworthy that current symptomatic relief for AD is provided by memantine, a metabotropic glutamate receptor antagonist. Therefore the astrocyte-specific EAATs offer an intriguing therapeutic target (68)(69)(70) for manipulating excessive glutamate levels as described in AD.…”

Ceftriaxone ameliorates tau pathology and cognitive decline via restoration of glial glutamate transporter in a mouse model of Alzheimer's disease

“…Its neurotransmission is tightly controlled by 5 different glutamate transporters within the vicinity of glutamatergic synapses in humans to prevent prolonged glutamate input and subsequent glutamate-induced excitotoxicity in neurons. Among these transporters, the excitatory amino acid transporter 2 or its mouse homologue glutamate transporter 1 (GLT-1, herein collectively referred to as GLT-1) expressed predominantly on astrocytes is responsible for regulating 90% of glutamate levels in the synapses (Kim et al, 2011). A significant reduction of GLT-1 activity has been reported to occur in an early stage of AD and correlates well with synaptic loss and cognitive decline in patients (Masliah et al, 1996).…”

Yin Yang 1 Is a Repressor of Glutamate Transporter EAAT2, and It Mediates Manganese-Induced Decrease of EAAT2 Expression in Astrocytes

“…Glutamate transporter dysfunction has been linked to neurological disorders, including stroke, epilepsy, amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Huntington's disease (HD), and Parkinson disease (PD) (reviewed in reference 3). In humans, among the five subtypes of Na ϩ -dependent glutamate transporters (excitatory amino acid transporters EAAT1 to EAAT5), EAAT1 and EAAT2, homologs of glutamate/aspartate transporter (GLAST) and GLT-1 in rodents, are preferentially expressed in astrocytes and considered the major transporters, with EAAT2 alone accounting for Ͼ80% of synaptic glutamate clearance (3,4). Since the dysregulation of EAAT2 is associated with various neurological disorders, understanding the regulatory mechanism of this transporter is critical for the development of therapeutics to mitigate glutamate-mediated pathologies (5).…”