Researchers at Trinity College Dublin have discovered that microglia, the brain’s main immune cells, play a key role in maintaining the stability of neural networks in Alzheimer’s disease. Importantly, this suggests that treatments that suppress these cells indiscriminately may be counterproductive.
Microglia are generally thought to promote Alzheimer’s disease by causing inflammation in the brain. However, this study was published in a major neurological journal brainfound that reducing the number and activity of these cells unexpectedly exacerbated abnormal electrical activity in the brain and increased seizure-like phenomena.
Alzheimer’s disease affects more than 55 million people worldwide and is the leading cause of dementia. Memory loss is its best-known symptom, but scientists are increasingly recognizing that the disease also disrupts the brain’s electrical activity, affecting how networks of neurons communicate with each other.
In a new study, researchers from Trinity University’s Department of Biochemistry and Immunology and School of Medicine examined these changes in a widely used mouse model of Alzheimer’s disease.
The study, led by PhD student Dr. Hugh Delaney, found that normal patterns of brain activity associated with learning and memory weaken, and abnormal electrical activity becomes more common. Some of these changes resemble the hyperactivity seen in epilepsy, which is increasingly recognized as an underappreciated feature of Alzheimer’s disease and may contribute to cognitive decline.
To test whether reducing microglial activity would improve brain function, the researchers treated mice with a drug that blocks the colony-stimulating factor 1 receptor (CSF1R), a target currently being investigated in experimental treatments for neurodegenerative diseases. The results were unexpected. The treatment reduced the number of microglial cells and partially protected connections between neurons, but did not improve memory performance. Instead, it led to a marked increase in abnormal electrical activity within brain networks, including more severe seizure-like phenomena.
The researchers also found evidence that the treatment reduced the ability of microglia to remove potentially problematic synaptic connections between neurons, suggesting that these immune cells may work to keep brain circuits stable and limit excessive neuronal activity during disease progression.
We expected that reducing microglial activation might improve the function of brain networks affected by Alzheimer’s disease. Instead, we found the opposite. When microglia are suppressed, the brain becomes more electrically unstable and prone to abnormal activity. ”
Professor Mark Cunningham, Professor of Physiology, Trinity School of Medicine, and senior author of the study
Co-senior author Professor Colm Cunningham, Professor of Neuroscience in Trinity University’s Department of Chemistry and Immunology, added: “Microglia are often seen as the cause of harmful inflammation in Alzheimer’s disease, but our findings show that the picture is more complex. These cells also perform important housekeeping functions that help maintain healthy brain activity. Interfering with these functions can have unintended consequences.”
What are the potential implications of this research?
This study is particularly important because therapies designed to alter microglial activity are currently being investigated as potential treatments for Alzheimer’s disease.
However, the researchers say their findings do not exclude the possibility that microglia may be a therapeutic target. Rather, they suggest that future treatments will need to distinguish between harmful inflammatory processes and the beneficial role microglia play in maintaining healthy brain function.
The study also strengthens the evidence that abnormal electrical activity in the brain is a key feature of Alzheimer’s disease and could be an important target for future treatments.
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Reference magazines:
Delaney, H.J. Others. (2026) CSF1R inhibition exacerbates gamma oscillation disruption and induces network hyperexcitation in APP/PS1 mice. brain. DOI: 10.1093/brain/awag147. https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awag147/8733843
