Targeting Excitatory Amino Acid Transporter 2 as a Treatment for Alzheimer’s Disease

Abstract

Alzheimer’s disease (AlzD) is a significant global health concern. Pathologically, AlzD is demarcated by beta-amyloid (βA) plaques and hyperphosphorylated tau aggregates. In AlzD, glutamate homeostasis is disrupted due to enhanced release and/or impaired reuptake of glutamate, events that lead to excitotoxicity. Excitatory amino acid transporter 2 (EAAT2) is expressed in multiple cell types of the neurovascular unit (NVU) including glial cells (i.e., astrocytes) and immune cells (i.e., microglia) and regulates synaptic glutamate concentrations as well as phagocytosis of βA proteins. We hypothesize that EAAT2 can be developed as a target for novel neuroprotective drugs. Therefore, we performed a focused screen of small molecule natural product compounds and currently marketed therapeutics using primary cultures of human microglia and primary cultures of human neurons. This screen resulted in identification of 13 novel compounds that could target EAAT2. Two of these compounds (designated EMTMSP and FTTA) were prioritized due to their neuroprotective and phagocytosis stimulatory effects. EMTMSP and FTTA were shown to stimulate EAAT2-mediated transport of [3H] glutamic acid and enhanced microglial phagocytosis of Aβ1-42 in primary cultures of human microglia. We also demonstrated that EMTMSP (0.25 mg/kg; i.p.; 28-day treatment) improved working memory and reduced Aβ1-40/Aβ1-42 brain levels in male and female 3xTg mice, an established AlzD model. Overall, our translational studies demonstrate the utility of developing EAAT2 as a molecular transporter target that can be exploited for drug discovery in the context of AlzD.