Glutamate transporter EAAT2 plays a critical role in the homeostatic regulation of extracellular glutamate levels. EAAT2 also plays an essential role in cognitive memory functions. However, loss of EAAT2 protein and function are commonly found in Alzheimer?s Disease (AD) patients and are an early event in disease pathology. We recently discovered that restoration of EAAT2 protein function by a novel brain-penetrant small molecule, which we previously identified as capable of increasing EAAT2 expression through translational activation, significantly improved cognitive functions and restored synaptic integrity in an APP mouse model of AD. We have actively optimized this compound series and identified a number of potent and orally bioavailable compounds. In this application, we seek support to move the project forward from optimized compounds to a clinical candidate. In Year 1, we will focus on identifying the lead molecule from a group of ten fully optimized compounds through a series of in vitro and in vivo efficacy, selectivity, and safety evaluations. In Years 2-3, we will focus on evaluation of the lead molecule in two AD models, APPSw,Ind mice and rTg(tauP301L)4510 mice, and identify the compound as the clinical candidate.

Public Health Relevance

A large number of studies have indicated that glutamate dyshomeostasis plays a crucial role in the pathogenesis of Alzheimer?s disease (AD). Glutamate transporter EAAT2 plays a critical role in the homeostatic regulation of extracellular glutamate levels. EAAT2 also plays an essential role in cognitive memory functions. Our groups have identified and developed a novel compound series that can effectively increase EAAT2 expression through translational activation. We have demonstrated that our compound provides profound efficacy in a mouse model of AD. In addition, a number of potent and orally bioavailable compounds have been identified. The purpose of this study is to move the project forward from optimized compounds to 'a clinical candidate'.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01AG054444-01A1
Application #
9310630
Study Section
Special Emphasis Panel (ZAG1)
Program Officer
Petanceska, Suzana
Project Start
2017-07-01
Project End
2020-05-31
Budget Start
2017-07-01
Budget End
2018-05-31
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Ohio State University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210