<< Back

2018 Alzheimer's Association Research Grant (AARG)

Molecular Profiling of glutamate and tau-mediated toxicity in AD

Could a new model reveal biological pathways in brain regions important for memory and learning that are harmed in Alzheimer’s?
 

Ana Pereira
Icahn School of Medicine at Mount Sinai
New York, NY - United States



Background

Nerve cells “talk” using specific kinds of chemical molecules called neurotransmitters. Scientists have found nerve cells that use one particular chemical, called glutamate, are more vulnerable to Alzheimer’s than nerve cells that use other chemicals for communication. Alzheimer’s could change levels of glutamate, over-exciting nerve cells and causing nerve cell damage, also known as “excitotoxicity.” Nerve cells are also vulnerable to toxic tau protein tangles, a hallmark brain change. Since both glutamate changes and tau tangles could lead to similar kinds of nerve cell death, it is possible that related molecular mechanisms underlie their harmful effects. These molecular mechanisms could represent novel therapeutic targets central to nerve cell death during Alzheimer’s.
 
A challenge in understanding how glutamate and tau protein contribute to nerve cell death is the variety of nerve cells in the brain. A special brain region called “hippocampus”, for example, is important for learning and memory and is highly susceptible to damage from Alzheimer’s. Yet it has many different nerve cell populations that function in distinct regions. Strategies that help tease apart how these nerve cell populations respond to toxicities caused by glutamate and tau changes could help explain why the region is so affected by Alzheimer’s.
 

Research Plan

Dr. Ana Pereira and colleagues will analyze overlapping biological (genetic and protein) pathways involved in nerve cell death caused by changes in glutamate levels and tau tangles. The researchers will develop a novel genetically-engineered Alzheimer’s-like mouse model for this study.  Dr. Pereira will create a new mouse model that combines an impairment of glutamate levels in the brain with the ability to specifically study one population of nerve cells in the hippocampus. The researchers will be able to track genetic and protein changes in this specific nerve cell population over time. They will then compare the changes to those seen in other Alzheimer’s-like mice with tau tangles in their brains, to identify common molecular mechanisms.
 
Dr. Pereira believes that their Alzheimer’s-like mouse model will reveal molecular pathways that lead to the over-excitement of these specific nerve cells and their subsequent damage in the special brain region. These pathways may overlap with mechanisms of tau-mediated nerve cell death, revealing central causes of nerve cell death during Alzheimer’s.
 

Impact

If successful, this study could reveal novel therapeutic targets to treat Alzheimer’s, particularly those that are closely related to nerve cell damage and loss. The study will also test the utility of cutting-edge genetic techniques that could allow other researchers to study how chemical molecules used for nerve cell communication could potentially affect specific nerve cell populations during Alzheimer’s.  
 

Back to Top