Talk abstracts
Talk on Tuesday 05:00-05:15pm submitted by Joshua Foster
A novel, small-molecule activator of glutamate transporter, EAAT2, translation delays disease progression in a tauopathy model of Alzheimer's disease
Joshua B. Foster (Department of Neuroscience), Chien-Liang Glenn Lin (Department of Neuroscience)
Abstract:
Alzheimer’s disease (AD) is a progressive neurological disease characterized by glutamate dyshomeostasis, amyloid-β plaques, tau-tangles, and progressive loss of cognitive functions. Current therapeutics are limited in efficacy and only provide temporary, palliative care. Therefore, there is need to develop novel therapeutics that can substantially slow or reverse disease progression. Glutamatergic transmission and synaptic concentration are elevated in AD patients. Excitatory amino acid transporter 2 (EAAT2) is responsible for clearing glutamate from the synaptic cleft and preventing excitotoxicity. However, many AD patients have reduced expression of EAAT2. We have developed a small-molecule compound series that is capable of increasing EAAT2 expression and previously shown that it has profound efficacy in an amyloid-β AD model. However, tau pathology is also involved in AD. Here, we evaluated the efficacy of an advanced compound in rTg4510 mice that only exhibit tau pathology. We hypothesize that long-term compound treatment will delay disease progression and improve synaptic integrity. rTg4510 mice were treated with LDN/OSU-214733 (10 mg/kg PO) from 2 months of age until 4 or 8 months of age before collecting behavioral and biochemical data. Four-month old compound-treated rTg4510 mice performed significantly better in cognitive tasks (novel object recognition/T-maze), a working memory test (Y-maze), and did not exhibit hyperactivity. Even at 8 months of age, treated rTg4510 mice performed significantly better in the Barnes maze and did not exhibit hyperactivity. Corroborating 8-month behavioral data, hippocampal long-term potentiation (LTP) in compound-treated rTg4510 mice was preserved. Biochemical and histological analysis are on-going, but preliminary data suggest that treatment may partially normalize EAAT2 protein levels and preserve synaptic integrity. This study suggests that modulation of EAAT2 expression is a viable therapeutic for the treatment of AD.
Keywords: EAAT2, Alzheimers disease, Drug discovery