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P3‐190: A NOVEL SMALL‐MOLECULE ACTIVATOR OF GLUTAMATE TRANSPORTER EAAT2 DELAYS DISEASE PROGRESSION IN A TAUOPATHY MODEL OF ALZHEIMER'S DISEASE
Author(s) -
Lin Chien-liang G.,
Foster Josh B.,
Zhao Fangli,
Lashley Rashelle,
Hodgetts Kevin,
Lin Lin
Publication year - 2018
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2018.06.1548
Subject(s) - tauopathy , long term potentiation , glutamate receptor , neuroscience , neurodegeneration , hippocampal formation , neurotoxicity , dementia , medicine , disease , pharmacology , chemistry , biology , toxicity , receptor
Background:Glutamate transporter EAAT2 plays a critical role in the maintenance of glutamate homeostasis in brain. Loss of EAAT2 protein and function are commonly found in Alzheimer’s disease (AD) patients. There is mounting evidence of glutamate dyshomeostasis on the pathogenesis of AD. We have developed a small-molecule compound series that is capable of increasing EAAT2 expression through a translational activation. Here, we evaluated the efficacy of an advanced compound in rTg(tauP301L)4510 mice that exhibit tau pathology. Methods: rTg4510mice were treated with the compound starting at 2-month (10 mg/kg/day). At 4-month old, mice were subjected to cognitive tests, including Y-maze, novel object recognition, and T-maze. At 8-month old, mice again were subjected to cognitive tests. Upon completion of behavioral testing, animals were euthanized for pathological studies. Results:Our compound was able to significantly reduce hyperactivity with agitative-like behavior, improve cognitive functions, increase hippocampal long-term potentiation (LTP), reduce neurodegeneration, reduce tau phosphorylation and neurofibrillary tangle, and reduce glial activation. Conclusions: This study suggests that modulation of EAAT2 expression is a viable therapeutic for the treatment of AD.