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Mobilizing Microglia in the Fight Against Alzheimer’s Disease

High magnification micrograph of microglia cells stained with Rio-Hortega's method (silver carbonate). This type is the ramified or resting microglia that appears in normal brain tissue.
Credit: iStock.
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At the Washington University School of Medicine in St. Louis, Dr. Marco Colonna, the Robert Rock Belliveau Professor of Pathology and Immunology, is exploring novel approaches to eliminate harmful amyloid plaques in Alzheimer’s disease (AD).

In their Science Translational Medicine study, Colonna and team suggest that a receptor expressed on the cell surface of microglia could be a potential new drug target for the disease.

Microglia are the brain’s resident immune cells. They respond to injury or disease, regulate neuronal development and help to clear harmful proteins. In AD, however, the cells show a degree of passivity. Colonna and colleagues have demonstrated that a specific receptor, expressed on the cell surface of microglia located close to amyloid plaques, could explain this unusual lack of activity.

APOE proteins in plaques bind to this receptor, called leukocyte Ig-like receptor B4 (LILRB4), and prevent microglia from controlling plaque formation. In animal models of AD, Colonna and team targeted LILRB4 with a homemade antibody, which blocked APOE from binding and reduced the number of Aβ plaques present in the mouse brain.

In an interview with Technology Networks, Colonna discusses the backstory of this research project, including the discovery of LILRB4 in macrophages, and its potential clinical relevance for AD drug development.

Molly Campbell (MC): Why are microglia are an interesting avenue of research for AD therapeutics?

Marco Colonna (MCo): AD stems from the accumulation of harmful amyloid plaques, resulting in gradual cognitive decline known as dementia. Microglia, the brain's immune cells, play a crucial role in clearing amyloid plaques and other debris, naturally impeding the advancement of AD.

MC: Can you discuss the current landscape of drug development in this space? Have any microglia-targeting therapeutics progressed to clinical trials?

(MCo): The US Food and Drug Administration has recently approved the first medications aimed at treating AD. These drugs are monoclonal antibodies designed to target the primary component of amyloid plaques, referred to as beta-amyloid.

They work by bolstering the ability of microglia to identify and diminish amyloid plaques, resulting in a moderate slowdown of cognitive decline. Additional therapeutics currently in clinical trial include agonists of the microglial receptor TREM2, a major activator of microglial functions.

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MC: Can you discuss how you discovered that microglia surrounding plaques produce and position the LILRB4 receptor on their cell surface, which inhibits their ability to control damaging plaque formation upon binding to APOE?

MCo: Back in 1997, we first identified LILRB4 and discovered that it is present on macrophages, which are immune cells found in various tissues throughout the body. Since then, we've been investigating how this receptor functions in the immune responses of macrophages, particularly in peripheral tissues. Recently, we shifted our focus to microglia, the brain's resident macrophages.

Our research was prompted by genetic data indicating that the genetic region containing LILRB4 is linked to an increased risk of developing AD and other neurodegenerative conditions. Additionally, when we analyzed the gene expression in mouse models with amyloid buildup in their brains, we observed high levels of LILRB4 expression in microglia responding to amyloid plaques.

Extending our investigation to human gene expression data, we discovered elevated LILRB4 expression in microglia from patients with AD. Furthermore, staining brain tissue samples revealed abundant LILRB4 expression in microglia clustered around amyloid plaques.

MC: How did you create an antibody that blocked APOE from binding to LILRB4, and what were the key findings when you delivered the antibody to mice?

MCo: To make this antibody, we vaccinated mice with a purified form of human LILRB4. The mice then produced antibodies against this protein, and we selected one of these antibodies because it was very good at binding human LILRB4. We then produced a large amount of this selected antibody.

Next, we injected this antibody into a mouse model with a build-up of harmful amyloid plaques in the brain. We found that when we repeatedly gave the mice this antibody, it reduced the amount of these plaques. Later on, we realized that one reason this antibody worked was because it blocked the interaction between LILRB4 and ApoE, which facilitates the formation of these plaques.

MC: There are some concerns surrounding therapeutics targeting microglia for AD – mostly relating to potential effects on the systemic immune system. Can you discuss your thoughts on this?

MCo: We should approach the use of this antibody with caution. Our expectation is that the antibody doesn't independently activate macrophages in the periphery but rather boosts the activity of already activated macrophages, enhancing their ability to engulf foreign substances. Our findings also suggest that this process of engulfing substances is linked with reduced inflammation, reducing the risk of unwanted inflammation.

Nevertheless, it's important to be wary of using this antibody and other antibodies that activate macrophages and microglia like antibodies that activate the microglial receptor TREM2.

MC: What are your next steps to advance this research?

MCo: We're investigating the effectiveness of an antibody in models of intraneural Tau aggregation, another key factor in AD. Additionally, we're exploring its potential in mouse models of other neurodegenerative disorders like Parkinson's disease, where toxic protein aggregates contribute to pathology. Microglia's role in clearing these aggregates and cellular debris motivates our interest in this antibody's broader therapeutic potential. Ultimately, we would like to acquire experimental evidence to support a potential clinical use of the antibody.

MC: What do you envision the short- and long-term future of developing therapeutics that target microglia in AD might look like?

MCo: The significance of targeting microglia in AD and other neurodegenerative diseases is evident in the ongoing use of anti-Abeta antibodies, both in clinical trials and outside settings, which rely on microglia's ability to clear harmful substances.

Clinical trials are also underway for antibodies that activate microglia by targeting TREM2. This growing body of research underscores the potential for leveraging microglia in effective short-term treatments for neurodegeneration. We eagerly anticipate clinical efficacy data, recognizing that early intervention holds the key to maximizing treatment effectiveness.

MC: Is there anything else that you wish to add?

MCo: We are grateful to the National Institutes of Health, Cure Alzheimer’s Fund and the Fred and Ginger Haberle Charitable Fund at the East Texas Communities Foundation for their generous support of our research. Their contributions are instrumental in driving forward therapeutic breakthroughs for AD patients.

Professor Maro Colonna was speaking to Molly Campbell, Senior Science Writer at Technology Networks.

About the interviewee:

Professor Marco Colonna was born in Parma, Italy, received his medical degree and specialization in internal medicine at Parma University, before completing his postdoctoral training at Harvard Medical School (Cambridge, Massachusetts, USA). He became a scientific member of the Basel Institute for Immunology (Basel, Switzerland). Since 2001 he has been a Professor of Pathology and Immunology at Washington University School of Medicine in St. Louis. Since, 2019 Dr. Colonna is a member of the National Academy of Science.