Researchers at Trinity College Dublin have discovered that microglia – the main immune cells of the brain – play a critical role in maintaining the stability of neuronal networks in Alzheimer's disease. Crucially, this suggests treatments that indiscriminately suppress these cells could be counterproductive.
Microglia, by driving brain inflammation, are generally considered to accelerate Alzheimer's disease. But the study, published in leading neurology journal Brain, found that reducing the number and activity of these cells unexpectedly worsened abnormal electrical activity in the brain and increased seizure-like events.
Alzheimer's disease affects more than 55 million people worldwide and is the leading cause of dementia. While memory loss is its best-known symptom, scientists increasingly recognise that the disease also disrupts the brain's electrical activity, affecting how networks of neurons communicate with one another.
In the new study, researchers from Trinity's School of Biochemistry and Immunology, and School of Medicine, examined these changes in a widely used mouse model of Alzheimer's disease.
The research, driven by PhD student Dr Hugh Delaney, revealed that normal patterns of brain activity associated with learning and memory became weaker, while abnormal electrical activity became more common. Some of these changes resembled the excessive activity seen in epilepsy, which is increasingly recognised as an underappreciated feature of Alzheimer's disease and may contribute to cognitive decline.
To test whether reducing microglial activity might improve brain function, the team treated mice with a drug that blocks "Colony Stimulating Factor 1 Receptor (CSF1R)", a target currently being explored in experimental treatments for neurodegenerative disease. The results were unexpected. Although the treatment reduced the number of microglial cells and partially protected connections between neurons, it did not improve memory performance. Instead, it led to a marked increase in abnormal electrical activity within brain networks, including more severe seizure-like events.
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 be working to keep brain circuits stable and to limit excessive neuronal activity during disease progression.
Professor Mark Cunningham, Professor of Physiology in Trinity's School of Medicine and senior author of the study, said: "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 were suppressed, the brain became more electrically unstable and more prone to abnormal activity."
Professor Colm Cunningham, Professor of Neuroscience in Trinity's School of Biochemistry and Immunology and co-senior author, added: "Microglia have often been viewed as drivers of harmful inflammation in Alzheimer's disease. Our findings indicate that the story is more complex. These cells are also performing important housekeeping functions that help maintain healthy brain activity. If we interfere with those functions, there may be unintended consequences."
What is the potential impact of this research?
The study is particularly significant because therapies designed to alter microglial activity are currently being investigated as potential treatments for Alzheimer's disease.
The researchers say their findings do not rule out microglia as a therapeutic target, however. Instead, they suggest that future treatments will need to distinguish between harmful inflammatory processes and the beneficial roles microglia play in maintaining healthy brain function.
The work also strengthens growing evidence that abnormal electrical activity in the brain is an important feature of Alzheimer's disease and may represent an important target for future therapies.
