Microglia Implicated in Alzheimer's Plaque Formation, Challenging Established Views

A new study led by researchers from VIB and KU Leuven indicates that immune cells known as microglia may actively contribute to the formation of plaques in Alzheimer's disease. This finding challenges the established perspective that these cells primarily act to prevent plaque accumulation. The groundbreaking research was recently published in PNAS.

"While many studies suggest microglia clean the brain and remove amyloid plaques, our research shows microglia are part of the problem and generate plaques."

Professor Joost Schymkowitz, a co-senior author from the VIB-KU Leuven Center for Neuroscience, further explained that plaques were previously thought to aggregate spontaneously. He added that it now appears microglia amplify the problem while attempting to address it.

Shifting the Paradigm on Alzheimer's Progression

Alzheimer's disease affects nearly 55 million people globally and is characterized by the accumulation of toxic protein aggregates known as amyloid plaques. These plaques are strongly linked to neuronal death and progressive dementia. For a long time, microglia have been considered protective against plaque buildup and have been a focus for several therapeutic strategies.

However, this study suggests microglia actively produce amyloid plaques in earlier stages of the disease, potentially influencing how Alzheimer's therapeutic strategies are developed.

The Mechanism of Cellular Plaque Generation

The research team demonstrated that microglia can convert soluble amyloid-beta (Aβ42) into extracellular fibrils with potent seeding activity. This is a crucial process by which one aggregate gives rise to multiple new ones. These cell-generated fibrils are similar to the structures that accumulate in the brains of Alzheimer's patients.

"Our results suggest many plaques in Alzheimer's brains might develop through cellular processes rather than spontaneous aggregation, indicating a previously unknown role for microglia."

Professor Frederic Rousseau, also a co-senior author, noted that using seeding assays, the team showed that cell-generated amyloid more closely resembles brain-derived amyloid. This new model triggers disease-relevant cellular responses, creating a more accurate representation of what occurs in patients.

This study highlights that microglia can actively produce amyloid-beta fibrils that are more similar to the plaques observed in patients. Professor Joost Schymkowitz mentioned that laboratory-formed amyloid structures often differ significantly from patient-derived structures, a distinction that has become clearer through recent research.

Implications for Future Therapeutic Strategies

By generating plaques in a model that more closely resembles those observed in patients, the researchers aim to improve understanding of how amyloid aggregates form and their atomic structure. This deeper insight into patient-derived structures will facilitate the design of more effective therapeutic targets.

Existing experimental therapies often aim to stimulate microglia to clear amyloid plaques. These new findings suggest that microglia's role might vary by disease stage, potentially contributing to plaque formation. This nuanced understanding could significantly influence how such therapies are developed and applied in the future.

Financial Support

The study received financial support from the Research Foundation Flanders (FWO), Queen Elisabeth Medical, Stichting Alzheimer Onderzoek - Fondation Recherche Alzheimer (STOPALZHEIMER.BE), the National Institutes of Ageing of the National Institutes of Health, KU Leuven, and VIB.