Alzheimer's Disease Linked to Altered 3D Genome Organization

Researchers have discovered that the three-dimensional (3D) organization of DNA is disrupted in brain cells affected by Alzheimer's disease. This disruption alters how important genes are activated and deactivated. The findings reveal a previously underexplored aspect of the disease.

The study, published in *Science*, involved scientists from Carnegie Mellon University, the University of Pittsburgh School of Medicine, and the University of Washington. They found that changes in genome folding correlate with shifts in gene activity and brain tissue organization. The team utilized single-cell technology, spatial mapping of brain tissue, and a new deep learning model to gather this information.

Deoxyribonucleic acid (DNA) folds into a complex 3D structure inside cells. This structure influences which genes are accessible and active. Changes in this physical organization can impact cell function. Researchers examined postmortem samples from the prefrontal cortex of individuals with and without Alzheimer's disease.

They used GAGE-seq, a technique that measures gene expression and 3D genome contacts within individual cells. These measurements were combined with spatial transcriptomic maps, which show where gene activity occurs in intact brain tissue. This allowed researchers to link genome organization with gene regulation and observe Alzheimer's-related molecular changes within the tissue.

The study identified consistent differences in the genome architecture of Alzheimer's cells. Large sections of the genome, normally organized into distinct active and inactive compartments, showed less defined boundaries. This pattern is described as “increased compartment mingling.” Several types of brain cells also exhibited fewer interactions between nearby genome sections and more contacts between distant regions.

Cells with increased compartment mingling tended to have lower overall gene activity. These structural differences were associated with reduced activity in neuronal and synaptic programs. They also showed changes in metabolism and cellular stress responses. The researchers also observed links to senescence-related programs in microglia, which are immune cells in the brain.