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2017 Grants - Llorens-Martín
Novel Methods to Interrogate the Subcellular Machinery of AD Models In Vivo
María Llorens-Martín, Ph.D.
Center for Networked Biomedical Research on Neurodegenerative Diseases
2017 Alzheimer's Association Research Grant (AARG)
Do brain cells important for learning and memory become altered in ways that lead to their premature death in Alzheimer's disease?
Certain areas of the healthy brain constantly generate new neurons (or nerve cells) throughout a person's lifetime. One such area is found in the hippocampus, a brain region vital for learning and memory. The process of generating new hippocampal neurons, called adult hippocampal neurogenesis, creates cells known as "newborn granule neurons." These cells help maintain the function of the entire cellular network in the hippocampus. During early stages of Alzheimer's disease, however, newborn granule neurons are especially vulnerable to damage and death — placing the hippocampal network at risk.
In preliminary research with hippocampal cells grown in a dish, María Llorens-Martín, Ph.D., and colleagues found that hippocampal neurogenesis became altered in Alzheimer's disease, producing abnormally structured granule neurons that died prematurely. This abnormality could also be induced by exposing hippocampal neurons to glycogen synthase-kinase-3 beta (GSK-3 beta), a protein linked to Alzheimer's. Such findings suggest that GSK-3 beta plays a key role in the brain damage seen in early Alzheimer's disease. However, scientists do not know the exact nature of this role, nor have they ever observed it in living brains.
For their present grant, Dr. Llorens-Martín and colleagues will examine how newborn granule neurons are affected in the brains of mice engineered to develop (1) Alzheimer's-like brain changes and (2) high levels of GSK-3 beta. Using state-of-the-art microscopes, they will visualize and assess exactly how GSK-3 beta affects the structure and function of granule neurons over their lifetime — and how it may induce their premature death. The researchers will also test a novel therapeutic approach for counteracting the effects of GSK-3 beta exposure. This technique will employ compounds designed to stimulate healthy activity in the dysfunctional neurons.
The results of this effort could refine our understanding of how newborn cells are damaged in the earliest stages of Alzheimer's disease. More importantly may suggest novel targets for future dementia therapies.