A new study led by researchers from VIB and KU Leuven reveals that immune cells in the brain known as microglia may actively promote the formation of plaques in Alzheimer’s disease. This challenges the long-standing assumption that these cells function solely as defenders that clear harmful buildup. The findings, recently published in Proceedings of the National Academy of Sciences, suggest that microglia may play a more complex and previously underappreciated role in disease development.
For decades, prevailing research has characterised microglia as protective cells tasked with removing amyloid plaques from the brain. However, this new work indicates that their role may be more paradoxical. According to co-senior author Joost Schymkowitz, microglia do not merely respond to plaque accumulation but may also contribute to it. Rather than plaques forming independently through spontaneous aggregation, the study suggests that microglial activity—while attempting to mitigate damage—may inadvertently amplify the very processes that drive plaque formation.
Alzheimer’s disease affects nearly 55 million people worldwide and is defined by the accumulation of toxic protein aggregates, commonly referred to as amyloid plaques, in the brain. These plaques are closely associated with neuronal damage, cognitive decline, and progressive dementia. Microglia have long been considered a key line of defence against this pathology and have therefore become a central focus of therapeutic strategies. Yet the new findings indicate that, particularly in earlier stages of the disease, microglia may also act as active contributors to plaque formation, prompting a reconsideration of current therapeutic approaches.
The research team demonstrated that microglia can transform soluble amyloid-beta proteins into structured fibrils with strong seeding activity. This seeding process is especially significant, as it allows a single aggregate to give rise to many more, accelerating disease progression. Notably, the fibrils generated by microglia resemble those found in the brains of patients, suggesting that cellular processes may play a more direct role in shaping disease pathology than previously understood.
Co-senior author Frederic Rousseau highlighted that these findings point to an additional, previously unrecognised function of microglia. Using seeding assays, the team showed that amyloid produced by cells more closely mimics patient-derived material and elicits biologically relevant responses. This represents an important advance, as it provides a model that better reflects the conditions occurring in human disease and may improve the relevance of experimental studies.
The study also underscores the limitations of traditional laboratory models, where amyloid plaques are typically formed under simplified conditions that differ significantly from those in patients. By developing approaches that generate plaques more representative of those observed in the human brain, researchers may gain deeper insight into the mechanisms of aggregation and identify more effective therapeutic targets. Importantly, while several experimental treatments aim to stimulate microglia to clear plaques, these new findings suggest that their effects may vary depending on the stage of the disease. This nuanced understanding could prove critical in refining future strategies for treating Alzheimer’s disease.
More information: Katerina Konstantoulea et al, Phagocytes as plaque catalysts: Human macrophages generate seeding-competent Aβ42 fibrils with cross-seeding activity, Proceedings of the National Academy of Sciences. DOI: 10.1073/pnas.2516774123
Journal information: Proceedings of the National Academy of Sciences Provided by Vlaams Instituut voor Biotechnologie
