Microglia: the double-edged sword in Alzheimer's progression

Microglia are known to play an important role in Alzheimer's disease, but exactly what they do has remained a mystery. Scientists in the Bart De Strooper Lab at the VIB-KU Leuven Center for Brain & Disease have unraveled the varying roles of microglia in Alzheimer's at different stages of the disease. Their research was published in Nature Communications.

Many of the risk genes for Alzheimer's point towards a central role of microglia, the macrophage cells that act as one of the main methods of immune defense in the central nervous system. Yet exactly how they play a role in the disease has remained unclear for scientists.

"The role of microglia in Alzheimer's has been puzzling for researchers due to contradictory findings of past studies." Nóra Baligács, first author of the paper and PhD researcher in the De Strooper Lab, explains. "Some hypothesized that microglia cleared amyloid-β (Aβ) plaques – the biological signature of Alzheimer's disease – from the brain, while others were convinced that microglia were involved in spreading Aβ to different parts of the brain."

Due to this discrepancy, researchers in the De Strooper Lab hypothesized that the role of microglia in Alzheimer's may depend on the stage of the disease. To test this, they used a drug to take away microglia from the brains of Alzheimer's mouse models, both before and after the formation of Aβ plaques.

Different roles in different stages

They found that when microglia were depleted before plaques were present, less plaques formed in the brains of these mice. This suggests that when microglia are present at an early stage, they are involved in creating plaques in the brain. However, when microglia were depleted after the formation of plaques, the plaques became more compact and less pathology was observed in neurons.

"From these experiments, we concluded that microglia do indeed have different functions at different stages at the disease: in the early stages, they perform a 'good' role and in the later stages a 'bad' one." Nóra Baligács shares. "But we didn't stop there – we were also curious to know why microglia do different things at different stages of Alzheimer's."

When they read existing research on this topic, the team discovered that in early stages of the disease, microglia are not yet activated. At the early stages, they're mostly homeostatic, and become activated only later on in the disease. They believed that these homeostatic microglia may be the ones responsible for spreading the plaques, while the activated ones may be the ones responsible for compacting them.

To test this, the lab transplanted human microglia into the Alzheimer's mouse model. These human microglia contained a risk gene that prevents microglia from responding and getting activated, making them homeostatic. The researchers found that in the Alzheimer's mouse models with the homeostatic microglia, there were more and bigger plaques in the brain, in addition to more pathological neurons.

"Our study confirms that homeostatic microglia play a detrimental role at the beginning of Alzheimer's disease, causing more plaques, while the activated microglia may provide a protective role later on in Alzheimer's." Bart De Strooper, group leader at the VIB-KU Leuven Center for Brain & Disease Research, concludes. "These findings clarify conflicting reports, confirm microglia as key drivers of amyloid pathology, and raise questions about optimal therapeutic strategies for the disease."

Publication

Homeostatic microglia initially seed and activated microglia later reshape amyloid plaques in Alzheimer’s Disease. Baligács, et al. Nature communications, 2024. DOI: 10.1038/s41467-024-54779-w.

Funding

The research (team) was supported by the Research Foundation Flanders (FWO), a Medical Research Grant, the European Research Council (ERC), a Methusalem grant, the Queen Elisabeth Medical Foundation for Neurosciences, the Opening the Future campaign of the Leuven Universitair Fonds, Stichting Alzheimer Onderzoek - Fondation Recherche Alzheimer (STOPALZHEIMER.BE), and the Alzheimer’s Association USA.