Glutamate Modulator Reverses Genetic Expressions of Aging and Alzheimer's Diease in Rodent Model

Neurological disease researchers have found that the glutamate modulator riluzole reversed gene expression profiles caused by age and Alzheimer’s disease (AD) in a rat AD model.

Glutamate is the most abundant excitatory neurotransmitter in the vertebrate nervous system. At chemical synapses, glutamate is stored in vesicles. Nerve impulses trigger release of glutamate from the presynaptic cell. Glutamate acts on ionotropic and metabotropic (G-protein coupled) receptors. In the opposing postsynaptic cell, glutamate receptors, such as the NMDA receptor or the AMPA receptor, bind glutamate and are activated. Because of its role in synaptic plasticity, glutamate is involved in cognitive functions such as learning and memory in the brain.

AD and age-related cognitive decline involve the hippocampus, a vulnerable brain region implicated in learning and memory. To understand the molecular effects of aging on the hippocampus, investigators at the Rockefeller University (New York, NY, USA) characterized the gene expression changes associated with aging in rodents using RNA-sequencing (RNA-seq) and then validated the expression changes using qRT–PCR open arrays.

The investigators reported in the March 29, 2016, online edition of the journal Molecular Psychiatry that the glutamate modulator, riluzole, which was recently shown to improve memory performance in aged rats, prevented many of the hippocampal age-related gene expression changes. Riluzole was known to increase the ability of the glutamate transporter EAAT2 (excitatory amino-acid transporter 2) to scavenge excess glutamate, regulating synaptic transmission. RNA-seq and immunohistochemistry confirmed an increase in EAAT2 expression in the hippocampus after riluzole treatment, identifying a possible mechanism underlying the improved memory function.

"In aging and Alzheimer's, the chemical signal glutamate can accumulate between neurons, damaging the circuitry," said first author Dr. Ana Pereira, instructor in clinical medicine at the Rockefeller University. "When we treated rats with riluzole, we saw a suite of changes. Perhaps most significantly, expression of molecules responsible for clearing excess glutamate returned to more youthful levels. We hope to use a medication to break the cycle of toxicity by which glutamate can damage the neurons that use it as a neurotransmitter, and our studies so far suggest that riluzole may be able to accomplish this. We found that in addition to recovering the expression of EAAT2, the drug restored genes critical for neural communication and plasticity, both of which decline with aging and even more significantly in Alzheimer's disease."

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