Researchers at Massachusetts General Hospital have discovered how a specific gene mutation in the brain’s immune cells may play a surprising role in Alzheimer’s disease (AD).
Their study, published in the journal Neuron, focuses on a gene called TREM2, which helps activate microglia—immune cells that clean up toxic waste in the brain, like amyloid plaques that build up between nerve cells.
In this study, the researchers looked at a particular mutation in the TREM2 gene, called T96K.
This is a “gain-of-function” mutation, which means it causes TREM2 to stay more active than normal.
At first, this might sound helpful, but the team wanted to know whether the constant over-activation could actually make Alzheimer’s worse.
To find out, they created a mouse model that carried the T96K mutation and also had signs of Alzheimer’s disease.
They discovered that in female mice only, the mutation actually weakened the microglia’s ability to respond to the harmful plaques. This means the immune cells were less able to protect the brain, even though the gene was more active.
The researchers combined several methods to study how the mutation affects microglial function.
They used genetic tools, special imaging techniques like confocal microscopy, and protein tests like ELISA to examine brain tissue. They also used single-cell RNA sequencing to track how the mutation changed microglia activity over time.
This is the first study to show that not only “loss-of-function” mutations (where genes are too weak) but also “gain-of-function” mutations (where genes are overactive) in TREM2 can increase the risk of Alzheimer’s. Specifically, the T96K mutation made microglia less able to clean up harmful plaques and reduced their protective response—especially in female mice.
These findings are important because they change how scientists think about TREM2. Until now, efforts to treat Alzheimer’s by boosting TREM2 activity seemed promising. But this study shows that in some cases, more activity isn’t better. Overactive TREM2 may actually make things worse.
The researchers say their work could help guide future treatments for Alzheimer’s that target TREM2 in smarter ways. Rather than simply turning the gene on or off, therapies may need to find the right balance.
Next, the team plans to study how TREM2 gain-of-function mutations affect immune system activity, fat metabolism in microglia, and aging. They’ll continue using both human cell models and Alzheimer’s mouse models to understand these processes better.
This research highlights how complex Alzheimer’s disease is and shows why personalized approaches to treatment may be the key to making real progress.
If you care about Alzheimer’s, please read studies about Scientists find the root cause of Alzheimer’s disease and findings of Alzheimer’s might not be primarily a brain disease. A new theory suggests it’s an autoimmune condition.
For more about Alzheimer’s disease, please read studies about These places in U.S. have the most cases of Alzheimer’s disease and findings of Scientists confirm the link between COVID-19 and Alzheimer’s disease.
The study is published in Neuron.
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