How Do Microglia Play a Role in Alzheimer’s Disease?

Microglia are specialized immune cells in the brain. While they normally protect our brains, they can also contribute to neurodegenerative diseases such as Alzheimer's. The exact mechanism behind this contribution is not yet fully understood due to the complexities involved in studying them in human brain samples. Now, a research team led by Prof. Bart De Strooper (UK-DRI@UCL and VIB-KU Leuven) and Prof. Renzo Mancuso (VIB-UAntwerp) made a xenotransplantation model – mice with stem-cell-derived human microglia in their brains to observe how human microglia respond to the disease environment. Their findings, published in Nature Neuroscience, will help scientists better understand the complex mechanisms involved in Alzheimer's disease.

Alzheimer's disease (AD) is a complex, progressive neurodegenerative disorder that affects millions of people worldwide. The World Health Organization predicts a tripling of cases by 2050, highlighting the urgent need for new treatments.

Microglia, our brain’s immune cells, are responsible for clearing debris and responding to inflammation in the brain. Scientists have been studying these cells in AD, as they play a central role in the disease, especially in the building-up of and early response to amyloid-β plaques, a hallmark of the disease. The microglia react to the plaques as they are perceived as foreign to the brain, making them the main drivers of the neuroinflammation that characterizes AD. Studying these cells in human brain samples post-mortem can be challenging because of genetic differences between people, the time between death and examination, and the presence of other brain disorders. Indeed, studies in human postmortem brain samples have shown mixed results regarding the reaction of microglia. It’s also not possible to test the effects of medication on post-mortem brains.

That is why the first authors of the study, Dr. Nicola Fattorelli and Dr. Anna Martinez Muriana, together with their colleagues at the VIB-KU Leuven Center for Brain & Disease Research, the VIB-UAntwerp Center for Molecular Neurology and the UK Dementia Research Institute, developed a unique mouse model. This xenotransplantation model is genetically engineered to mimic the amyloid-β plaque accumulations seen in humans with AD and can be transplanted stem-cell-derived human microglia. Previously, a similar model was able to show how transplanted human neurons die in AD. Now, this approach allowed the researchers to investigate how human microglia respond to amyloid plaques during the course of the disease.

Reference: Mancuso R, Fattorelli N, Martinez-Muriana A, et al. Xenografted human microglia display diverse transcriptomic states in response to Alzheimer’s disease-related amyloid-β pathology. Nat Neurosci. 2024. doi: 10.1038/s41593-024-01600-y

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