Scientists have identified several gene mutations that cause or contribute to the onset of Alzheimer’s disease. But many scientists suspect that other DNA changes may help lead to Alzheimer’s-related brain cell damage and lead to symptoms of confusion and memory loss in patients.
In particular, scientists want to understand how segments of DNA that jump around in the genome – so-called transposable elements – affect Alzheimer’s disease. A five-year, $9 million grant from the National Institute on Aging of the National Institutes of Health (NIH) will fund research led by several researchers at the Washington University School of Medicine in St. Louis and at the University of Texas at San Antonio. answer that question.
Transposable elements are thought to come from very old viruses and bacteria that infected our ancestors millions of years ago. This foreign DNA became intertwined with the human genome, although not directly part of it. Transposable elements, first discovered in the 1940s, have been linked to diseases such as hemophilia, Duchenne muscular dystrophy, a predisposition to cancer and, more recently, Alzheimer’s disease.
“We want to characterize the DNA changes that these transposable elements contribute to, and we want to understand whether certain gene-altering techniques can block the dysregulation associated with these transposable elements to stop or delay Alzheimer’s pathology,” said Carlos Cruchaga, PhD. investigator in the Department of Psychiatry at the University of Washington. “We are integrating data from human cells and from animal models to fully understand and characterize these changes.”
Cruchaga, the Barbara Burton and Reuben M. Morriss III Professor, is one of four University of Washington principal investigators involved in the new research effort. Cruchaga’s lab studies tissue from the brains of deceased participants in the Dominantly Inherited Alzheimer Network (DIAN) project. These participants had genetic mutations that guaranteed they would develop early-onset Alzheimer’s disease.
Cruchaga’s lab will also study stem cells that turn into neurons in culture. These neurons will have mutations in various Alzheimer’s-causing genes. The goal is to compare newly formed neurons that have the mutations with much older neurons taken from the brains of DIAN study participants to determine whether some of the damage associated with these changes can be prevented or reversed.
Andrew Yoo, PhD, associate professor of developmental biology, pioneered the technique of generating senescent neurons from skin biopsies. Skin cells are made into stem cells, which can then be treated with various factors to become neurons. This project will study neurons derived from skin from individuals with specific mutations 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 are also associated with genetic variants that increase the risk of Alzheimer’s disease. Her lab will study how transposable elements may contribute to microglial damage that may drive Alzheimer’s pathology.
Ting Wang, PhD, the Sanford and Karen Lowentheil Professor of Medicine, is one of the world’s leading experts in the study of transposable elements and epigenetic changes in a range of disorders. Unlike mutations, epigenetic changes are caused by modified gene expression rather than changes in the genetic code itself. Because they do not change the DNA sequence of the genome, they could be reversible.
“Characterizing transposable element changes is complex and requires expertise in many fields,” Cruchaga explained. “The Wang lab will analyze and quantify what happens to transposable elements in cells that will be studied by all of our labs.”
The lead researchers will also incorporate DNA changes present in tissue from human brains, as well as microglia and neurons in culture, into the fruit fly model. These experiments will be led by Bess Frost, PhD, at UT-San Antonio. In flies, changes and damage caused by transposable elements appear much faster than in other animal models, and scientists will be able to use genetic tools such as CRISPR to edit changes caused by transposable elements to see if they can be reversed. or delay Alzheimer’s pathology.
“The ultimate goal is to target transposable elements in a therapeutic way,” Cruchaga said. “We don’t believe that transposable elements trigger the disease. But once they’re activated, we think they can accelerate the events that cause neuronal death. If we can block transposable elements, we can delay the disease process.”
Washington University School of Medicine
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