Case Western Reserve University researchers find protein associated with brain cell death

Cleveland -- Neuroscientists at the Case Western Reserve University School of Medicine have found evidence of which protein in the brain's immune cells triggers a cascade of reactions that produces unregulated free radical production that eventually leads to the neural cell death found in Alzheimer's disease.

They report their findings in the Journal of Biological Chemistry article, "Fibrillar Beta-Amyloid Stimulated Intracellular Signaling Cascades Require Vav for Induction of Respiratory Burst and Phagocytosis in Monocytes and Microglia."

The researchers discuss the role that the multi-domain protein Vav plays in the intercellular signaling of microglia, the brain's primary immune cell, when it produces an inflammatory response when coming into contact with beta-amyloid fibrils that form the harmful brain plaque.

The primary goal of this study was to evaluate potential signaling intermediates upstream from the oxidation, said the researchers. They had an interest in a group of signaling molecules (guanine nucleotides exchange factors) that are known to activate oxidation. Vav was selected from the group for study.

The inflammatory response that arise when the microglia connects with the plaque has been suspected as producing the oxidative damage observed in both human and animal models of AD, report the researchers.

This current study builds on prior research studies that produced evidence of the microglia mounting this inflammatory immune response by whittling down the various components in that reaction.

"We have recently shown that microglia employ a multi-receptor cell surface complex to detect and respond to amyloid –beta fibrils," the researchers write. "These receptor elements act in concert to stimulate intercellular signaling cascades as well as initiate a novel type of phagocytosis (cell death) in microglia."

"Vav has been found to be the key regulatory element within the intercellular signaling cascade," said Brandy Wilkinson, the study's lead researcher. Her co-investigators are Jessica Koenigsknecht-Talboo, Christian Grommes, C.Y. Daniel Lee and Gary Landreth from the Alzheimer Research Laboratory in the Case department of neuroscience. Vav also plays a critical role in the initial microglial response to the plaque.

Oxidative damage has long been suspected as playing an early critical role in AD. Because the events that trigger the beginnings of AD are still unknown, the Case researchers began targeting research on the reaction between the plaque and immune cells.

In in vitro studies of brain tissue from mice, the researchers found that the microglia had the appropriate immune response that the plaque was harmful, but then the protein Vav was found to be a component in oxidative damage since elimination of the protein resulted in reduced free radical production.

Wilkinson said by understanding this biological component in the disease process, it holds the potential to "push back the severity of the disease" by developing new drugs that specifically target the component causing the most destruction and decreasing the possibility of injuring or interrupting other biological processes.

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This research was supported by grants from the National Institutes of Health, the Blanchette Hooker Rockefeller Foundation and the American Health Assistance Foundation. Wilkinson also had funding through the NIH's Ruth L. Kirschstein Naitonal Research Service Award.

The research was being presented during a poster session at the International Conference on Alzheimer's Disease and Related Disorders in Madrid, Spain.

Case Western Reserve University is among the nation's leading research institutions. Founded in 1826 and shaped by the unique merger of the Case Institute of Technology and Western Reserve University, Case is distinguished by its strengths in education, research, service, and experiential learning. Located in Cleveland, Case offers nationally recognized programs in the Arts and Sciences, Dental Medicine, Engineering, Law, Management, Medicine, Nursing, and Social Work. http://www.case.edu.


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