Scientists have identified a handful of genetic mutations that cause or contribute to the onset of Alzheimer’s disease. But many scientists suspect that other DNA changes may contribute to damage to brain cells linked to Alzheimer’s disease and lead to symptoms of confusion and memory loss in patients.
In particular, the researchers want to understand how the DNA segments that jump around in the genome – the so-called transposable elements – influence Alzheimer’s disease. A five-year, $9 million grant from the National Institutes of Health (NIH) National Institute on Aging will fund research by several researchers at Washington University School of Medicine in St. Louis and the University of Texas in San Antonio to answer this question.
Transposable elements are believed to originate from very ancient viruses and bacteria that infected our ancestors millions of years ago. This foreign DNA has become intertwined with the human genome, although it is not exactly part of it. Discovered in the 1940s, transposable elements have been linked to diseases such as haemophilia, Duchenne muscular dystrophy, a predisposition to cancer and, more recently, Alzheimer’s disease.
“We want to characterize the DNA modifications to which these transposable elements contribute, and we want to understand whether certain genetic modification techniques can block the dysregulation associated with these transposable elements to arrest or delay Alzheimer’s pathology,” said Carlos Cruchaga. , PhD, research director in the Department of Psychiatry at the University of Washington. “We are integrating data from human cells and animal models to fully understand and characterize these changes.”
Cruchaga, Professor Barbara Burton and Reuben M. Morriss III, is one of four University of Washington principal investigators involved in the new research effort. The Cruchaga lab is studying brain tissue from deceased participants as part of the Dominantly Inherited Alzheimer Network (DIAN) project. These participants had genetic mutations that virtually guaranteed they would develop Alzheimer’s disease at an early stage.
Cruchaga’s lab will also study stem cells that will be transformed into neurons in culture. These neurons will have mutations in various genes responsible for Alzheimer’s disease. The goal is to compare newly made neurons that have mutations to much older neurons taken from the brains of participants in DIAN studies to determine if some of the damage associated with these changes can be prevented or reversed.
Andrew Yoo, PhD, associate professor of developmental biology, has developed a technique to create aging neurons from skin biopsies. Skin cells are transformed into stem cells, which can then be treated with various factors to become neurons. As part of this project, neurons derived from the skin of individuals carrying specific mutations will be studied in order to identify transposable changes that may contribute to Alzheimer’s disease.
Celeste Karch, PhD, associate professor of psychiatry, will focus on brain cells called microglia, which have also been linked to genetic variants that increase the risk of Alzheimer’s disease. His lab will investigate how transposable elements might contribute to microglia damage that can lead to Alzheimer’s disease.
Ting Wang, Ph.D., Sanford and Karen Lowentheil Professor Emeritus of Medicine, is one of the world’s leading experts in the study of transposable elements and epigenetic changes in a number of disorders. Unlike mutations, epigenetic changes are caused by altered expression of genes rather than alterations in the genetic code itself. Because they do not alter the DNA sequence of the genome, they could be reversible.
“Characterizing transposable element changes is complex and requires expertise in many areas,” Cruchaga explained. “Wang’s lab will analyze and quantify what happens with transposable elements in cells that all of our labs will study.”
Principal investigators will also incorporate DNA modifications found in human brain tissue, as well as cultured microglia and neurons, into a fruit fly model. These experiments will be led by Bess Frost, PhD, at UT-San Antonio. In flies, the changes and damage caused by transposable elements will appear much faster than in other animal models, and researchers will be able to use genetic tools, such as CRISPR, to modify the alterations caused by transposable elements in order to see if it is possible to change or delay the pathology of Alzheimer’s.
“The ultimate goal is to target transposable elements therapeutically,” Cruchaga said. “We don’t think transposable elements trigger the disease. But once activated, we believe they can accelerate events that cause neuronal death. If we can block transposable elements, we could delay the disease process.
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