A genetic mutation affecting microglia, the brain’s immune cells, has been found to increase the risk of developing Alzheimer’s disease by up to threefold. The mutation, known as TREM2 R47H/+, impairs microglia function and contributes to Alzheimer’s pathology by causing inflammation, reducing debris clearance, impairing response to neuronal injury, and leading to excessive synapse pruning.
Researchers from The Picower Institute for Learning and Memory at MIT conducted a study that focused on human microglia cell cultures with the R47H/+ mutation. They found that the mutant microglia exhibited several deficits related to Alzheimer’s disease pathology, including increased inflammation, reduced debris clearance, impaired response to neuronal injury, and excessive synapse pruning.
The study used a stem cell line derived from a healthy 75-year-old woman, in which the researchers used CRISPR gene editing to insert the R47H/+ mutation. They then cultured both edited and unedited stem cells to become microglia, providing them with a supply of mutated microglia and healthy microglia for comparison.
The team found that microglia with the mutation increased their expression of genes associated with inflammation and immune responses, and demonstrated a significantly more pronounced inflammatory response when exposed to simulated infection. Furthermore, the mutant microglia cleared less debris and were less likely to respond to neuronal injury compared to normal microglia.
To test how the mutant microglia act in a living brain, the researchers transplanted mutant or healthy control microglia into mice in a memory-focused region of the brain called the hippocampus. They found significant reductions in synaptic proteins in mice where the mutated microglia were implanted, indicating excessive synapse pruning.
The study highlights the complex impact of the TREM2 R47H/+ mutation, offering insights for potential therapeutic interventions in Alzheimer’s disease. This research provides new insights into the molecular mechanisms underlying microglial dysfunction and potential therapeutic targets for the development of new treatments for Alzheimer’s disease.
The study was funded by The Robert A. and Renee Belfer Family Foundation, The Cure Alzheimer’s Fund, the National Institutes of Health, The JPB Foundation, The Picower Institute for Learning and Memory, and the Human Frontier Science Program. The findings were published in the journal GLIA.