Researchers 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.
Dr James Murray, of Swansea University Medical School, is part of the research team whose findings have just been published in the journal Brain.
Microglia are usually thought of as drivers of the inflammation seen in Alzheimer's disease, and several experimental treatments aim to reduce their number or activity.
In this study, led by a team at Trinity College Dublin, mice were treated with a drug called GW2580, which blocks a receptor called CSF1R and reduces microglial numbers. The treatment did partially protect connections between neurons, but it did not improve memory, and it increased abnormal, epilepsy-like electrical activity in the brain.
The results suggest microglia are also doing some useful housekeeping work in the diseased brain, and that removing them altogether may cause problems of its own.
The work has its roots in a PhD studentship from almost ten years ago. In 2016, Dr Murray, then based at Trinity College Dublin's School of Biochemistry and Immunology, and Professor Colm Cunningham were awarded a Government of Ireland Postgraduate Scholarship by the Irish Research Council to fund a PhD for Sadia Islam, looking at how CSF1R signalling affects the behaviour of microglia. Dr Islam carried out much of the early laboratory work on CSF1R inhibition in the same APP/PS1 mouse model used in this paper and is a co-author on the study.
That early work was later taken further by another Trinity researcher, Hugh Delaney, who added detailed recordings of brain electrical activity and found the effect on network hyperexcitability that is the main finding of the paper.
Dr Murray, who has continued to collaborate with colleagues at Trinity College Dublin since moving to Swansea University, said: “Sadia and I worked on this together with Colm Cunningham when I was at Trinity, looking at how blocking CSF1R changes what microglia do.
"It's satisfying to see that project come out the other end as a paper, even though I'd moved to Swansea by the time it was finished.
“The main finding, that cutting down microglia can make brain activity less stable rather than more, is a useful caution for the development of treatments that target these cells. It isn't as simple as fewer microglia being better.”
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 the findings do not rule this out, but they suggest any such treatment will need to separate the harmful, inflammatory side of microglial activity from the more protective, housekeeping roles these cells also seem to play.