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2008 Grants - Sheen
In Vitro Modeling of Neuronal-Glial Interactions in Alzheimer's Disease
Volney Sheen, M.D., Ph.D.
Beth Israel Deaconess Medical Center
2008 New Investigator Research Grant
The brain comprises nerve cells (neurons) and a variety of supporting cells, some of which are called glial cells. Neurons and glial cells interact in a number of important ways, some of which influence susceptibility to inflammation or diseases, such as Alzheimer's disease. For example, death of nerve cells often leads to inflammation in nearby glial cells. One consequence of such inflammation is increased secretion of the protein S100B by glial cells. Some evidence suggests that S100B may, in turn, act on other neurons to cause additional dysfunction and possible cell death.
The genes for S100B and amyloid precursor protein (APP), a key player in Alzheimer toxicity, are both found on chromosome 21. Chromosome 21 is significant because an extra copy of this chromosome is the cause of Down syndrome. Correspondingly, individuals with Down syndrome exhibit the pathologic features of Alzheimer's disease at a young age.
Volney Sheen, M.D., Ph.D., and colleagues are studying interactions between the glial protein S100B and the neuronal protein APP. They have found evidence that overexpression of both proteins may contribute to neuronal death by acting through a shared biochemical pathway.
Dr. Sheen and colleagues plan to extend their studies of this interaction using cultured neural stem cells derived from individuals with Down syndrome. They will test whether the effects of S100B and APP are mediated by the same or interacting pathways. Eventually, they plan to study whether other genes contained on chromosome 21 also contribute to Alzheimer-like pathology in these cells. Their studies may help clarify the role of Down syndrome genes in causing Alzheimer-like pathology and neurodegeneration. They may also reveal insights into the role of neuron-glial interactions in neurodegeneration.