Genetic data may lead to future Alzheimer’s treatments

(CN) – In a development that could shed light on possible treatment, researchers have found that Alzheimer’s disease appears to reshape the way a patient’s genetic material is physically organized within brain cells.

In a study published on Thursday in Scienceresearchers at Carnegie Mellon University’s School of Computer Science and the University of Pittsburgh School of Medicine found that the disease may involve changes in the three-dimensional organization of DNA within brain cells.

The research reveals a previously underexplored aspect of Alzheimer’s disease biology that shows how the genetic architecture is organized differently in some brain cells of people with the disease.

The researchers found that the genome rearrangement was linked to changes in genetic activity and the way brain cells were arranged. The research relied heavily on mapping the folds 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 3D structure of the genome is a fundamental regulatory layer that helps link DNA sequence to gene activity. By integrating genome folding, cellular state and tissue context, we can move beyond cataloging disease-associated changes to understanding how they fit together and which mechanisms to test next.”

The researchers used single-cell technology, spatial mapping of brain tissue, and a new deep learning computational model for the study.

The researchers analyzed postmortem tissue from the prefrontal cortex of the brain that was donated by people who participated in a long-term dementia study. The research team used a method known as GAGE-seq to measure the activity and behavior of the genome in a single cell.

The researchers combined these measurements with spatial mapping of brain tissue to correlate the three-dimensional genome organization with 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 signatures in DNA, but also by how the genome folds in three dimensions within the nucleus,” the scientists wrote in the study. “How this three-dimensional genome organization changes in (Alzheimer’s disease) and how such changes correlate with cell-type-specific gene dysregulation in the human brain remains 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 in the University of Pittsburgh’s Department of Neurobiology. “We know the classic hallmarks of Alzheimer’s disease—the accumulation of amyloid-beta plaques and tau tangles—but our results establish higher-level chromatin changes 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 of Alzheimer’s or other types of dementia.

“Measuring gene activity and genome folding in the same cell allows us to directly link chromosome structure to disease-related gene programs,” said Yang Zhang, a project scientist at Carnegie Mellon University who co-led the research. “Across several brain cell types, this paired view revealed a consistent signature of 3D genome rearrangement in Alzheimer’s disease and helped us prioritize regulatory regions for future mechanistic and therapeutic investigation.”

The study involved researchers from the Broad Institutes of MIT and Harvard, the University of California at Los Angeles, the University of Washington and the Rush Alzheimer’s Disease Center.