Researchers receive $9 million grant to study how jumping genes influence Alzheimer's disease

Researchers receive $9 million grant to study how jumping genes influence Alzheimer's disease

Scientists have identified a handful of gene mutations that cause or contribute to the onset of Alzheimer's disease. But many scientists suspect that other DNA changes could help drive Alzheimer's-related damage to brain cells, leading to symptoms of confusion and memory loss in patients.

In particular, the researchers want to understand what influence sections of DNA that bounce around in the genome - so-called transposable elements - have on 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 the University of Texas at San Antonio. Answer this question.

Transposable elements are thought to come from very ancient viruses and bacteria that infected our ancestors millions of years ago. This foreign DNA became intertwined with the human genome, although it was not necessarily part of it. Transposable elements were first discovered in the 1940s and have been linked to diseases such as hemophilia, Duchenne muscular dystrophy, a predisposition to cancer and, more recently, Alzheimer's disease.

We would like to characterize the DNA changes to which these transposable elements contribute and we would like to understand whether some gene editing techniques can block the dysregulation associated with these transposable elements to stop or delay Alzheimer's pathology. We integrate data from human cells and animal models to fully understand and characterize these changes.”

Carlos Cruchaga, PhD, senior researcher, Department of Psychiatry, Washington University

Cruchaga, the Barbara Burton and Reuben M. Morriss III Professor, is one of four Washington University principal investigators involved in the new research effort. The Cruchaga laboratory studies tissue from the brains of deceased participants in the Dominantly Inherited Alzheimer Network (DIAN) project. These participants had genetic mutations that almost guaranteed they would develop early-onset Alzheimer's disease.

Cruchaga's lab will also study stem cells that are processed into neurons in cultures. These neurons have mutations in various Alzheimer's-causing genes. The goal is to compare the newly formed neurons that have mutations with the much older neurons taken from the brains of participants in the DIAN studies to see if some of the damage associated with these changes can be prevented or reversed.

Andrew Yoo, PhD, associate professor of developmental biology, developed a technique to create aging neurons from skin biopsies. The skin cells are processed into stem cells, which can then be treated with various factors to become neurons. This project will examine skin-derived neurons from individuals with specific mutations to identify transmissible 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. Her lab will study how transposable elements might contribute to microglial damage that could trigger Alzheimer's pathology.

Ting Wang, PhD, the Sanford and Karen Lowentheil Distinguished Professor of Medicine, is one of the world's experts in studying transposable elements and epigenetic changes in a range of diseases. Unlike mutations, epigenetic changes are caused by altered expression of genes rather than changes in the genetic code itself. Since they do not change the DNA sequence of the genome, they could be reversible.

“Characterizing transposable elemental changes is complex and requires expertise in many areas,” Cruchaga explained. “The Wang lab will analyze and quantify what happens to transposable elements in cells, which all of our labs will study.”

The principal investigators will also integrate the DNA changes in human brain tissue, as well as microglia and neurons in culture, into a fruit fly model. These experiments are led by Bess Frost, PhD, at UT-San Antonio. In flies, changes and damage caused by transposable elements occur much more quickly than in other animal models, and researchers will be able to use genetic tools such as CRISPR to modify changes caused by transposable elements to see if it is possible to change or delay Alzheimer's pathology.

“The ultimate goal is to target transposable elements in a therapeutic way,” Cruchaga said. "We don't think transposable elements trigger the disease. But once they are activated, we think they can accelerate events that cause neurons to die. If we can block the transposable elements, we could delay the disease process."

Source:

Washington University School of Medicine

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