Enhancing Glutamate Levels as a Way to Treat Alzheimer’s Disease

Ana Pereira, MD
Icahn School of Medicine at Mount Sinai (New York, NY)
Year Awarded:
2016
Grant Duration:
July 1, 2016 to June 30, 2019
Disease:
Alzheimer's Disease
Award Amount:
$300,000
Grant Reference ID:
A2016478S
Award Type:
Standard
Award Region:
US Northeastern

This grant is made possible in part by the support from the Ping Y. Tai Foundation.

Ana Pereira, MD

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

Summary

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.

Details

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.

About the Researcher

Dr. Ana C. Pereira graduated in medicine from Universidade Federal de Sao Paulo, Brazil, in the top one percent of the class. She was a post-doctoral research scientist at Columbia University, at the Taub Institute for Alzheimer’s Disease, investigating adult neurogenesis with brain imaging techniques in animals and humans. She completed a residency in neurology at Harvard University and received subspecialty training in cognitive neurology at Columbia University. She is currently an assistant professor of neurology and neuroscience at the Icahn School of Medicine at Mount Sinai, where she has been studying the susceptibility of glutamatergic neural circuits to age-related cognitive decline and Alzheimer’s disease (AD), along with potential therapeutic interventions. Her studies have used animal models, structural analysis with confocal and electron microscopy, behavioral assays, and RNA sequencing. They have been accompanied by parallel translational and clinical studies in patients with AD and sleep-disordered breathing, with use of state-of-the art neuroimaging techniques and neuropsychological measures.

Personal Story

During medical school, I read and translated (from English into Portuguese) a few chapters of the major book “Principles of Neural Science,” by Kandel, Schwartz and Jessell. I realized that the brain was so complex and its neural circuitry was so precise that neuroscience research appealed to me as very interesting for a career of discoveries ahead.

I have also always been interested in humanities (literature, arts etc.) and I also thought that studying the biology of cognition would help us understand emotions, thoughts, memories, and insights, and ultimately to have a grasp on creativity. Neuroscience seemed to me to be an important bridge between sciences and humanities (as has been pointed out by E. O. Wilson and Eric Kandel), as well as providing a novel and modern framework for “The Two Cultures” exposed by C.P. Snow.

After medical school, I went to Columbia University, where I worked in the laboratory on neurogenesis and imaging techniques. That was a landmark experience for me, as the environment in the lab was so enthusiastic, and doing research and making discoveries was so thrilling, that it left me with no doubt that a career in neuroscience research could only be an exciting and fulfilling one.

Next, I went to Harvard University to be trained as a neurologist. After residency, I decided to focus on further understanding the pathophysiology of the disease that mostly affects cognition, Alzheimer’s disease. As a cognitive neurologist who has seen numerous patients suffering with Alzheimer’s disease, I have been committed to translating important laboratory findings into clinical studies that can lead to novel and more effective treatments for this devastating disorder.

Publications

Sharma A, Kazim SF, Larson CS, Ramakrishnan A, Gray JD, McEwen BS, Rosenberg PA, Shen L, Pereira AC. Divergent roles of astrocytic versus neuronal EAAT2 deficiency on cognition and overlap with aging and Alzheimer's molecular signatures. Proc Natl Acad Sci U S A. 2019 Oct 22;116(43):21800-21811. doi: 10.1073/pnas.1903566116. Epub 2019 Oct 7. PubMed PMID: 31591195 PubMed Icon Google Scholar Icon

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