title: Restored glial glutamate transporter EAAT2 function as a potential therapeutic approach for Alzheimer's disease.
abstract: Glutamatergic systems play a critical role in cognitive functions and are known to be defective in Alzheimer's disease (AD) patients. 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. In the current study, we investigated whether restored EAAT2 protein and function could benefit cognitive functions and pathology in APPSw,Ind mice, an animal model of AD. A transgenic mouse approach via crossing EAAT2 transgenic mice with APPSw,Ind. mice and a pharmacological approach using a novel EAAT2 translational activator, LDN/OSU-0212320, were conducted. Findings from both approaches demonstrated that restored EAAT2 protein function significantly improved cognitive functions, restored synaptic integrity, and reduced amyloid plaques. Importantly, the observed benefits were sustained one month after compound treatment cessation, suggesting that EAAT2 is a potential disease modifier with therapeutic potential for AD.
authors.affiliation: Department of Neuroscience, The Ohio State University, Columbus, OH 43210.
authors.forename: Kou
authors.initials: K
authors.lastname: Takahashi
authors.affiliation: Department of Neuroscience, The Ohio State University, Columbus, OH 43210.
authors.forename: Qiongman
authors.initials: Q
authors.lastname: Kong
authors.affiliation: Department of Neuroscience, The Ohio State University, Columbus, OH 43210 lin.492@osu.edu.
authors.forename: Yuchen
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Department of Neuroscience, The Ohio State University, Columbus, OH 43210.
authors.forename: Nathan
authors.initials: N
authors.lastname: Stouffer
authors.affiliation: Department of Neuroscience, The Ohio State University, Columbus, OH 43210.
authors.forename: Delanie A
authors.initials: DA
authors.lastname: Schulte
authors.affiliation: Department of Neuroscience, The Ohio State University, Columbus, OH 43210.
authors.forename: Liching
authors.initials: L
authors.lastname: Lai
authors.affiliation: Department of Neuroscience, The Ohio State University, Columbus, OH 43210.
authors.forename: Qibing
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Neuroscience, The Ohio State University, Columbus, OH 43210.
authors.forename: Ling-Chu
authors.initials: LC
authors.lastname: Chang
authors.affiliation: Department of Neuroscience, The Ohio State University, Columbus, OH 43210.
authors.forename: Sky
authors.initials: S
authors.lastname: Dominguez
authors.affiliation: Laboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115.
authors.forename: Xuechao
authors.initials: X
authors.lastname: Xing
authors.affiliation: Laboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115 Department of Pharmacological and Pharmaceutical Sciences, University of Houston College of Pharmacy, Houston, TX 77004.
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Cuny
authors.affiliation: Laboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Hodgetts
authors.affiliation: Laboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115.
authors.forename: Marcie A
authors.initials: MA
authors.lastname: Glicksman
authors.affiliation: Department of Neuroscience, The Ohio State University, Columbus, OH 43210 lin.492@osu.edu.
authors.forename: Chien-Liang Glenn
authors.initials: CL
authors.lastname: Lin
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D003071:Cognition / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D027342:Excitatory Amino Acid Transporter 2 / Q000235:genetics / Q000378:metabolism*; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D058225:Plaque, Amyloid / Q000235:genetics / Q000378:metabolism; D011724:Pyridazines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*
chemical_list: D016229:Amyloid beta-Peptides; D027342:Excitatory Amino Acid Transporter 2; C588183:LDN-OSU-0212320; D011724:Pyridazines; D011725:Pyridines; C493396:Slc1a2 protein, mouse