GLT-1 Pathophysiological Mechanisms and as a Target to Treat Alzheimer's Disease

Glutamate is a chemical that allows neurons to communicate; a critically important feature for memory. Glutamate needs to be at the correct place and time to allow efficient neuronal communication and to avoid toxicity. Glutamate levels are regulated by the glutamate transporter 1 (GLT-1), which is a protein that plays the important role of regulating concentrations of glutamate in the brain’s extracellular space by transporting it, along with other ions, across cellular membranes. This proposal investigates the mechanisms through which GLT-1 becomes dysregulated using several techniques. These experiments may allow development of novel medications that can bring GLT-1’s function closer to normal levels and significantly benefit Alzheimer’s patients.

Our project studies how dysfunction of the major glutamate transporter in the brain, GLT-1, is an important mechanism in several toxicities in Alzheimer’s disease (AD), thus potentially validating GLT-1 as a novel and specific target for drug development.

The neurons most susceptible to death from AD are the ones that use glutamate as a neurotransmitter (chemical messengers that enable neurotransmission). Glutamate is the major excitatory neurotransmitter in the brain and its regulation is critical for learning and memory. When glutamate is not located in the correct place and amount, it causes several deleterious effects to neurons that can ultimately lead to cell death. Importantly, the glutamate transporter GLT-1 is the dominant regulator of glutamate levels and it is highly depressed in AD. GLT-1 plays the important role of regulating concentrations of glutamate in the brain’s extracellular space by transporting it, along with other ions, across cellular membranes. Furthermore, glutamatergic dysregulation is implicated in several other pathological mechanisms in AD, including the release and toxicities of the proteins amyloid-beta (which forms amyloid plaques) and tau (which forms neurofibrillary tangles). Better regulation of glutamatergic neural circuits is critically important to effectively treat age-related cognitive decline and AD.

Our proposal investigates GLT-1’s pathology in aging and AD by first, quantifying changes at the synaptic level, with behavior and gene expression in an Alzheimer’s mouse model. We also plan to intervene with a GLT-1-enhancer. Moreover, our project uses a newly developed mouse model to study GLT-1’s impact on gene expression patterns and behavior in the aging and Alzheimer’s brains under GLT-1 enhancement. These integrated aims will help explain the impact of varying GLT-1 levels in the aging and Alzheimer’s brains at the structural, molecular and functional levels.

In summary, the proposal utilizes a unique, multi-modal, integrative and innovative investigative approach to test a mechanistic hypothesis that ultimately can result in development of new and more effective treatments for age-related cognitive decline and AD, using GLT-1 as a specific target for drug development.