Restored glial glutamate transporter EAAT2 function as a potential therapeutic approach for Alzheimer's disease

The excitatory amino acid transporter 2 (EAAT2) plays a critical role in the maintenance of low extracellular glutamate levels. Previous literature has indicated that glial glutamate transporter EAAT2 plays an essential role in cognitive functions and that loss of EAAT2 protein is a common phenomenon observed in AD patients and animal models. To determine whether the loss of EAAT2 contributes to AD, one group of researchers crossed mice lacking one allele for EAAT2 with AβPPswe/PS1ΔE9 mice and found accelerated cognitive deficits in the crossed mice. These findings suggest that decreased EAAT2 levels may contribute to AD. In this report the authors aimed to investigate whether  restored EAAT2 protein levels and function could ameliorate AD-like behavior and pathology in mice and whether EAAT2 is a potential therapeutic target for AD. To achieve these aims EAAT2 transgenic mice having a 1.5–2-fold increase in EAAT2 protein levels were crossed with J20 Tg mouse model of AD. The crossed mice exhibited restored EAAT2 protein levels and function and, most importantly, significantly improved cognitive functions, restored synaptic integrity, and reduced amyloid plaques. Next, J20 mice were treated with a novel brain-penetrant small molecule, LDN/OSU-0212320, which we previously identified as capable of increasing EAAT2 expression through translational activation. Significantly, the authors found that this compound can restore EAAT2 function and ameliorate AD-like behavior and pathology.