Scientists have identified a few genetic mutations that cause or contribute to Alzheimer’s disease. But many scientists suspect that other changes in DNA may help cause Alzheimer’s-related damage to brain cells and lead to the symptoms of confusion and memory loss that patients experience.
In particular, the researchers want to understand how the bits of DNA circulating in the genome – the 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 Washington University School of Medicine in St. Louis and at the University of Texas at San Antonio to answer this question.
The transposable elements are believed to have come from very ancient viruses and bacteria that infected our ancestors millions of years ago. This strange DNA has become tangled up in the human genome, though not exactly part of it. Convertible elements were first discovered in the 1940s and have been linked to diseases such as hemophilia, Duchenne muscular dystrophy, a predisposition to cancer and, most 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 may prevent the dysregulation associated with these transposable elements to stop or delay Alzheimer’s disease,” he said. Carlos Cruchaga, Ph.D., Principal Investigator in the Department of Psychiatry at the University of Washington. “We are integrating data from human cells and animal models to fully understand and describe these changes.”
Cruchaga, Barbara Burton Professor and Reuben M. Morriss III, is one of four University of Washington principal investigators participating in the new research effort. Cruchaga’s lab studies brain tissue from deceased participants in Predominantly Inherited Alzheimer’s Network (DIAN) Draft. These participants had genetic mutations that all ensured early development of Alzheimer’s disease.
Cruchaga’s lab will also study stem cells that will be converted into neurons in culture. These neurons will have mutations in the various genes that cause Alzheimer’s disease. The goal is to compare the newly synthesized neurons containing the mutations with much older neurons taken from the brains of participants in the DIAN studies to determine if some of the damage associated with these changes could be prevented or reversed.
Andrew Yu, Ph.D., associate professor of developmental biology, pioneered a technique for creating aging neurons from skin biopsies. The skin cells are converted into stem cells, which can then be treated with various agents to become nerve cells. As part of this project, skin-derived neurons from individuals with certain mutations will be studied to determine the reversible changes that may contribute to Alzheimer’s disease.
Celeste Karch, Ph.D.The assistant 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. Her lab will study how transposable elements can contribute to microglia damage that may lead to Alzheimer’s disease.
Ting Wang, Ph.D., Sanford Distinguished Professor of Medicine and Karen Lowenthill, is one of the world’s experts in the study of transposable elements and epigenetic changes in a number of disorders. Unlike mutations, epigenetic changes occur due to altered expression of genes rather than changes in the genetic code itself. Because they do not change the DNA sequence of the genome, they can be reversible.
Cruchaga explained that “Describing transposable element changes is complex and requires expertise in many areas.” “Wang’s lab will analyze and determine what happens with transposable elements in cells that all of our labs will study.”
The lead researchers will also incorporate DNA changes found in tissues from human brains, as well as microglia and neurons in culture, into a Drosophila model. These experiments will be led by Pace Frost, Ph.D., at UT-San Antonio. In flies, 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 tweak the modifications caused by transposable elements to see if they can be altered. or delay Alzheimer’s pathology.
“The ultimate goal is to target transposable elements in a therapeutic manner,” Kroshaga said. We do not believe that convertible items lead to the onset of disease. But once activated, we think it can speed up the events that cause neurons to die. If we can prevent transmissible items, we may delay the disease process.”