Microglia, the brain's resident immune cells, do not just clear amyloid plaques - they can help build them. That is the conclusion of a study led by researchers at VIB and KU Leuven, published in PNAS, which found that microglia remodel soluble amyloid-beta (Abeta42) into extracellular fibrils with potent seeding activity, the same kind of structures found in the brains of people with Alzheimer's disease.
Seeding is what makes amyloid pathology so hard to contain: one aggregate gives rise to many more, spreading damage through the brain. The Leuven team's finding suggests microglia are not passive bystanders to that process in the earlier stages of disease but participants in it. "Most studies suggest that microglia are there to clean up the brain and remove the amyloid plaques. What we discovered is that actually they're part of the problem. They generate plaques", said Prof. Joost Schymkowitz, co-senior author at the VIB-KU Leuven Center for Neuroscience. He added that plaques were assumed to aggregate on their own, and that microglia, in trying to handle the problem, appear to amplify it.
The practical stakes are considerable. Alzheimer's affects close to 55 million people worldwide, and microglia have been treated as protective allies - the target of several experimental therapies aimed at boosting their plaque-clearing capacity. If these cells also manufacture seeding-competent fibrils, then revving up microglial activity could cut both ways, and the therapeutic logic may need rethinking.
The work reframes microglia as double agents rather than simple defenders, particularly early in the disease course. That distinction matters for drug developers deciding when, and in which direction, to nudge the brain's immune response.