In brief

Two distinct subpopulations of macrophages in the brains of Alzheimer’s patients could serve as valuable therapeutic targets to reduce inflammation.

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Brain immunity through the ages

28 Apr 2023

A new analytical platform reveals signature changes in immune cells of the brain during aging and neurodegenerative conditions such as Alzheimer’s disease.

Certain aspects of childhood are retained in us through adult life, such as food preference, personality traits, hobbies and interests. Similarly, a unique immune cell in the brain, microglia, also persists throughout the many chapters of our lives, from early embryonic development to old age.

Microglia, which are brain-resident macrophages, keep the complex neural circuitry running like clockwork by eliminating damaged cells, clearing infectious agents, and fine-tuning cell-to-cell connections. Recent studies have revealed that microglia encompasses an incredibly diverse collection of highly specialised subtypes, though the precise function of each group has remained obscure.

The origin of some neurodegenerative conditions such as Alzheimer’s disease can be traced back to faulty microglia, said Aymeric Silvin, an Associate Postdoctoral Researcher at A*STAR’s Singapore Immunology Network (SIgN). The dysregulation of microglia engenders a build-up of protein aggregates and inflammatory markers that block neural pathways, he explained.

“A better understanding of microglia heterogeneity and function in neurodegenerative diseases is crucial for developing therapeutical strategies to remove these aggregates and dampen inflammation,” he said.

In an ambitious effort to map the vast universe of microglia subtypes one cell at a time, Silvin and a team of researchers, led by Florent Ginhoux, a Senior Principal Investigator at SIgN, built their analytical platform by merging six large datasets from single-cell RNA sequencing studies.

They called it the M-Verse—a first-of-its-kind online tool that serves to map microglial subpopulations in the developing mouse brain, from foetus to adult, and in models of Alzheimer’s disease.

Using the M-Verse tool, they found two distinct classes of disease-associated microglia, or DAMs, which had a yin-and-yang effect on the aging brain. One group of DAMs is protective, while the other, termed TREM2-independent disease inflammatory macrophages (DIMs), stoked the fires of inflammation associated with neurodegenerative disease.

Silvin said that the ‘good’ microglia reactivated processes used during early foetal development in a bid to lessen the inflammatory damage in the brain. “Through the M-Verse, we observed that TREM-2 dependent DAMs reacquired a programme used naturally during embryogenesis to ensure proper brain development,” said Silvin, adding that this likely mirrors what happens in the ageing human brain.

The M-Verse provides researchers with a glimpse of valuable future therapeutic targets based on the specific cell surface proteins associated with Alzheimer’s disease. The team has patented this technology as part of their commercialisation efforts.

“We could design antibody therapies that target these proteins,” suggested Silvin, adding that this approach has been used extensively (and successfully) to treat cancer by other research groups. For now, the team is exploring the subtle signals put out by microglia to dial down inflammation and investigating potential strategies to remove aggregates in the ageing brain.

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Silvin A., Uderhardt S., Piot C., Da Mesquita S., Yang K., et al. Dual ontogeny of disease-associated microglia and disease inflammatory macrophages in aging and neurodegeneration. Immunity. 2022 Aug 9;55(8):1448-1465.e6. │article

About the Researchers

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Florent Ginhoux

Senior Principal Investigator

Singapore Immunology Network (SIgN)
Florent Ginhoux is Senior Principal Investigator at the Singapore Immunology Network (SIgN), A*STAR. He obtained his PhD in 2004 from the University Pierre et Marie Curie, Paris VI. As a postdoctoral fellow, he joined the Laboratory of Miriam Merad in the Mount Sinai School of Medicine (MSSM), New York, where he studied the ontogeny and the homeostasis of cutaneous dendritic cell populations, with a strong focus on Langerhans cells and Microglia. In 2008, he became an Assistant Professor in the Department of Gene and Cell Medicine, MSSM and member of the Immunology Institute of MSSM. He joined SIgN in May 2009 as a Principal Investigator before becoming Senior Principal Investigator in 2017. He has been a Web of Science Highly Cited Researcher since 2016, and an EMBO member since 2022. Ginhoux is also an Adjunct Visiting Associate Professor in the Shanghai Immunology Institute, Jiao Tong University, as well as Adjunct Associate Professor in the Translational Immunology Institute, SingHealth and Duke NUS. He is now a laboratory director in Gustave Roussy Hospital, Villejuif, France. His new laboratory focuses on paediatric cancers.
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Aymeric Silvin

Associate Postdoctoral Researcher

Singapore Immunology Network (SIgN)
Aymeric Silvin received his PhD degree in 2011 from the University Pierre et Marie CURIE (UPMC), where he also completed his postdoctoral research. He joined A*STAR’s Singapore Immunology Network (SIgN) in 2016 as an Associate Postdoctoral Researcher. His research interests revolve around macrophages in health and disease.

This article was made for A*STAR Research by Wildtype Media Group