A new study led by researchers at VIB and the University of Leuven shows that immune cells called microglia may actively promote plaque formation in Alzheimer’s disease, challenging the long-held view that these cells act only as defenders against plaque buildup. The results of this study were recently published in PNAS.
“Most studies suggest that microglia are there to cleanse the brain and remove amyloid plaques. What we found is that microglia are actually part of the problem. Microglia produce plaques,” said Professor Joost Simkowitz, co-senior author of the study from VIB-KU Leuven Neuroscience Center. “Plaque was thought to aggregate on its own, and it appears that microglia are amplifying it in an attempt to deal with the problem.”
Alzheimer’s disease affects approximately 55 million people worldwide and is characterized by the buildup of toxic protein aggregates in the brain known as amyloid plaques. These plaques are associated with nerve cell death and progressive dementia. Brain microglia have attracted attention for their role in preventing plaque buildup in this disease and are the focus of several treatments. Nevertheless, this study shows how microglia are active producers of amyloid plaques during the early stages of the disease and reconsiders the treatment paradigm for Alzheimer’s disease.
Functional dichotomy of microglia
The research team showed that microglia can reassemble soluble amyloid beta (Aβ42) into extracellular fibrils with strong disseminating activity (seeding is a key problem in disease and is the process by which one aggregate gives rise to multiple new aggregates). These are the same types of structures that accumulate in the brains of Alzheimer’s patients.
“Our results suggest that many plaques in Alzheimer’s brains may arise through cellular processes rather than spontaneous aggregation. We believe this highlights a second role for microglia that we were unaware of until now,” added Professor Frédéric Rousseau, co-senior author of the study from the VIB-KU Leuven Neuroscience Center. “Using seeding assays, we showed that the amyloid produced in cells more closely resembles brain-derived amyloid and triggers disease-related cellular responses, establishing a model that better reflects what is happening inside the patient’s body.”
A better model to study the early stages of Alzheimer’s disease
This study shows that microglia can actively generate amyloid beta fibrils that more closely resemble the plaques observed in patients.
“We have been studying amyloid plaques in the laboratory for a long time. They form spontaneously in small vials. However, when researchers started analyzing the amyloid structures obtained from patients, it became clear that these structures were significantly different from those that form in a laboratory environment,” said Professor Jost Simkowitz.
“We are now better able to generate plaques in models that more closely resemble those observed in patients. By understanding how amyloid aggregates form in patients and what their atomic structure looks like, we can design more effective strategies to target them therapeutically.”
Several experimental treatments aim to stimulate microglia to clear amyloid plaques. New findings suggest that depending on the stage of the disease, microglia may also contribute to plaque formation, and this insight could influence how such treatments are designed.
funding
This study was supported by funding from the Flanders Research Foundation (FWO), the Queen Elizabeth Medical, the Stichting Alzheimer-Onderszog Alzheimer Foundation Recherche Alzheimer Foundation (STOPALZHEIMER.BE), the National Institute on Aging of the National Institutes of Health, the University of Leuven, and VIB.
sauce:
Flemish Institute of Biotechnology VIB
Reference magazines:
Constantulea, K. others. (2026) Phagocytes as plaque catalysts: human macrophages produce seeding-competent Aβ42 fibrils with cross-seeding activity. PNAS. DOI 10.1073/pnas.2516774123. https://www.pnas.org/doi/10.1073/pnas.2516774123
