Genetic clue could lead to future Alzheimer’s treatments

Researchers posit that changes in the three-dimensional structure of DNA inside brain cells may play a key role in Alzheimer's disease.(CN) — In a development that could shed light on potential treatment, researchers found Alzheimer’s disease appears to reshape how a patient’s genetic material is physically organized inside brain cells.In a study published Thursday in Science, researchers at Carnegie Mellon University’s School of Computer Science and the University of Pittsburgh School of Medicine discovered that the disease may involve changes in the three-dimensional organization of DNA inside brain cells.The research uncovers a previously underexplored aspect of Alzheimer’s disease biology that shows how genetic architecture is organized differently in certain brain cells of people with the disease.Researchers found that reorganization of the genome was linked to changes in genetic activity and in how brain cells were arranged. The research relied heavily on mapping the folding of genomes, which are the genetic instructions of all living organisms.“Alzheimer’s disease cannot be understood one layer at a time,” said Jian Ma, a professor of computational biology at Carnegie Mellon University, who led the study. “The genome’s 3D structure is a fundamental regulatory layer that helps to connect DNA sequence to gene activity. By integrating genome folding, cell state and tissue context, we can move beyond cataloging disease-associated changes toward understanding how they fit together and which mechanisms to test next.”Researchers used single-cell technology, spatial mapping of brain tissue and a new deep learning computational model for the study.The researchers analyzed post-mortem tissue from the prefrontal cortex of the brain that was donated from people who participated in a long-term study on dementia. The research team used a method known as GAGE-seq to measure genome activity and behavior in a single cell.Researchers combined these measurements with spatial mapping of the brain tissue to relate three-dimensional genome organization to gene regulation.The research team also relied on the use of Hicformer, an artificial intelligence model that can predict gene activity in different types of cells.“Gene activity is controlled not only by DNA sequence and chemical marks on DNA but also by how the genome is folded in three dimensions inside the nucleus,” the scientists write in the study. “How this three-dimensional genome organization changes in [Alzheimer’s disease] and how such changes relate to cell type-specific gene dysregulation in the human brain remain poorly understood.”The findings provide a framework for future studies to determine potential Alzheimer’s disease therapies.“Our study represents a major advance in understanding what goes wrong in Alzheimer’s disease,” said Hansruedi Mathys, an assistant professor of neurobiology at the University of Pittsburgh’s Department of Neurobiology. “We know the classic hallmarks of Alzheimer’s disease — accumulation of amyloid-beta plaques and tau tangles — but our results establish higher-order chromatin alterations as a component of the molecular pathology associated with the disease, which currently affects 7 million Americans, a number that continues to grow.”Alzheimer’s disease is the most common cause of dementia and affects more than 7 million Americans, according to the Alzheimer’s Association. It is estimated that one in three older adults will die with Alzheimer’s or other types of dementia.“Measuring gene activity and genome folding in the same cell allows us to directly connect chromosome structure with disease-related gene programs,” said Yang Zhang, a project scientist at Carnegie Mellon University who co-led the research. “Across several kinds of brain cells, this paired view revealed a consistent signature of 3D genome reorganization in Alzheimer’s disease and helped us prioritize regulatory regions for future mechanistic and therapeutic investigation.”The study included researchers from the Broad Institute of MIT and Harvard, University of California Los Angeles, the University of Washington and the Rush Alzheimer’s Disease Center.Categories / Health, ScienceSubscribe to our free newslettersOur weekly newsletter Closing Arguments offers the latest about ongoing trials, major litigation and rulings in courthouses around the U.S. and the world, while the monthly Under the Lights dishes the legal dirt from Hollywood, sports, Big Tech and the arts.Additional Reads