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2014 Grants - Shulman
Genome Instability as a Novel Link between Aging and Alzheimer’s Disease
Joshua Shulman, Ph.D.
Baylor College of Medicine
2014 New Investigator Research Grant
Alzheimer’s disease is a progressive brain disorder for which age is the key risk factor. Recent studies have found that as people age, their genomes — the complete set of genes in cells — can become vulnerable to alteration. Structural elements of DNA (genetic material) can “change position” within the genome. The mobilization of these elements, called transposable elements (TEs), may stimulate the expression of harmful gene variations that potentially promote brain cell damage.
In preliminary studies, Joshua Shulman, Ph.D., and colleagues observed possible links between harmful TE activity and abnormal tau protein. Abnormal tau tends to accumulate in the brain forming neurofibrillary tangles, a hallmark of Alzheimer’s disease. These tangles may hinder the ability of cells to communicate with one another and contribute to brain cell death. The researchers found that in fruit flies engineered to develop Alzheimer’s-like symptoms, abnormal tau promotes the age-associated activation of TEs in brain cells. Since the genomes of fruit flies are similar to those in people, fruit flies can provide a good model to study the relationship between tau and genome instability that may also exist in human brains.
For their current grant, Dr. Shulman and colleagues will perform more extensive studies in fruit flies and also examine the role of TEs in brain tissue from people who had Alzheimer’s disease. First, they will determine the precise levels of different classes of TE activity in their flies and human brain samples. Then, using the human brain tissue, they will look for genetic mechanisms that underlie abnormal TE function during aging — and explore how these mechanisms may be linked to brain damage involving tau, beta-amyloid and other Alzheimer’s-related molecules. The researchers will also test whether they can moderate abnormal tau and beta-amyloid activity in their flies by “turning off” genes that promote TE function. Collectively, the results of this effort could shed new light on why aging is such an important risk factor for Alzheimer’s disease and other neurodegenerative diseases. This research may also identify novel genetic pathways for exploration as potential therapies for these disorders.