Astrocyte Glutamate Transporter EAAT2 in Alzheimer Dementia

Abstract

Glutamate is an amino acid and also the major synaptic signaling molecule of neurons, essential in cognition, learning, and memory. Glutamate is neurotoxic. As soon as the glutamate signaling starts it is stopped in one millisecond by astrocytes, which take up and clear glutamate from the synapses, and prevent extended glutamate signaling, which can cause synapse loss and neuron cell death. Astrocytes express EAAT2 (excitatory amino acid transporter-2), the major glutamate transporter and 1% of brain protein. In Alzheimer dementia, brain has less EAAT2. In experimental Alzheimer mouse models, decreasing EAAT2 expression enhances dementia progression, and increasing EAAT2 expression slows dementia progression. These and other data indicate EAAT2 as a novel drug target in the treatment and prevention of Alzheimer dementia. In this chapter, after a brief revisit of Alzheimer research and clinical trials, synaptic glutamate signaling and EAAT2, I argue why EAAT2 drugs make therapeutic sense, and then describe a simple drug screening assay how to find them, by targeting the EAAT2 protein reconstituted in liposomes.