Dr James Murray
Photo Credit: Courtesy of Swansea University
Scientific Frontline: Extended "At a Glance" Summary: Microglia and Neuronal Stability in Alzheimer's Disease
The Core Concept: Microglia, the primary immune cells of the brain, play a critical protective role in maintaining the stability of neuronal networks, challenging the traditional view that they act solely as drivers of neuroinflammation in Alzheimer's disease.
Key Distinction/Mechanism: While current experimental Alzheimer's treatments frequently attempt to reduce microglial numbers or activity by blocking the colony stimulating factor 1 receptor (CSF1R), this indiscriminate suppression increases abnormal, epilepsy-like electrical hyperexcitability in the brain and fails to improve memory.
Major Frameworks/Components:
- Microglia: The resident macrophage cells of the central nervous system that perform vital neuroprotective "housekeeping" tasks alongside their inflammatory responses.
- CSF1R Inhibition: The pharmacological targeting of the CSF1R receptor (using the drug GW2580) to deplete microglial populations.
- Network Hyperexcitability: The destabilization of brain electrical activity, leading to epilepsy-like events, which occurs when protective immune cells are removed.
- APP/PS1 Mouse Model: A well-established transgenic animal model used to study the pathological progression of Alzheimer's disease in vivo.
Branch of Science: Neuroscience, Neuroimmunology, and Neuropharmacology.
Future Application: The development of highly targeted Alzheimer's therapeutics that selectively neutralize the harmful inflammatory actions of microglia while preserving their essential regulatory and stabilizing functions.
Why It Matters: This study serves as a critical caution for neuropharmacological development, demonstrating that the total suppression of brain immune cells could be counterproductive and actively harmful to patients suffering from neurodegenerative diseases.
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 that treatments indiscriminately suppressing 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 that 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 fellowship 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 signaling affects the behavior 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 of 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 that 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.
Published in journal: Brain
Authors: Hugh J Delaney, Sadia Islam, Dáire Healy, Ross Oglesby, Meghamsh Konda, Gudo M Rietman, Rebecca Lynch, Arshed Nazmi, James T Murray, Mark O Cunningham, and Colm Cunningham
Source/Credit: Swansea University
Edited by: Scientific Frontline
Reference Number: ns072826_01