Fellowship for Farr: Characterizing the Role of Glutamate Transporter 1 on Astrocyte Physiology in Alzheimer's Disease

Alzheimer’s disease (AD) inflicts significant private, community, and societal burdens by impairing cognitive function. The likely foundation for cognitive dysfunction in AD is synaptic impairment, characterized in part by glutamate-dependent hyperexcitability. Astrocytes lose capacity to regulate glutamate in AD, including by a reduction and/or dysfunction of the astrocytic glutamate transporter EAAT2/Glt-1. Glt-1 removes glutamate from the extracellular milieu, providing a primary defense against excitotoxicity while also driving electrochemical gradients that promote glycolysis and lactate release. Normalization of Glt-1, such as by treatment with pharmacological agents that increase Glt-1 expression, has been shown to protect synaptic proteins, improve basal synaptic strength, and improve cognition. However, the sufficiency of astrocytic Glt-1 to independently restore neuronal function has not been shown. Furthermore, the effect of Glt-1 on the astrocyte-neuron lactate shuttle in AD is unknown despite a clear mechanistic link between the two processes. Therefore, Aim 1 will test the hypothesis that normalization of Glt-1, using an astrocyte-specific AAV vector, will restore astrocyte-neuron coupling. In addition to the effect of Glt-1 on neurons, Glt-1 may also ameliorate excitotoxic damage to the structural barrier between vascular endothelium and perivascular astrocyte endfeet. Although excitotoxicity has been shown to damage astrocyte-vessel function, including via neuronal calcium dysregulation, the role of Glt-1 is unknown. To investigate the potentially protective role of Glt-1 on astrocyte-vessel interactions, Aim 2 will test the hypothesis that normalization of Glt-1 will restore cerebral blood flow, neurovascular coupling, and bloodbrain barrier leakiness. Aim 3 will establish the sufficiency of astrocytic Glt-1 to ameliorate neuronal hyperexcitability and to restore neuronal network connectivity, synchronicity, and neural density by altering calcium signaling. The objectives of the research will be to explicate the physiologic mechanism of astrocytic Glt- 1 and to spur development of astrocyte-directed approaches to treat Alzheimer’s disease. The primary goal of the fellowship will be to equip the trainee with skills necessary for further research training and for a successful independent research career measuring similar endpoints using basic and translational neuroimaging techniques. Execution of that goal will be achieved through a comprehensive training plan and a mentoring team of world-renowned experts from the Sanders-Brown Center on Aging. The trainee will develop expertise in communication of research results and networking, complex data analyses, rigorous research design and cutting-edge techniques such as electrochemistry, electrophysiology, and intravital imaging in the mouse. A tailored training and career development plan will facilitate the trainee’s ultimate translation of those skills to solve vital research questions in the neurodegeneration field. These skills and excellent mentorship therefore represent an outstanding opportunity to develop the trainee towards alleviating dementia as an independent physician-scientist.