Immune cells named microglia reside in the brain to perform housekeeping and protective functions. Signals from neurons, astrocytes and other brain cells inform microglia when there is material to be addressed and how aggressive that response should be. Microglia can thus recognize that the sticky bundles of amyloid beta that accumulate in Alzheimer’s disease do not belong in a healthy brain, and so they surround and clear them away. In Alzheimer’s disease, the microglia do not perform adequately, allowing the amyloid plaque bundles to continue to accumulate.

When an antibody that blocks APOE from binding to a receptor molecule on microglia, called LILRB4, was used, microglia resumed their normal function, engulfing and clearing the amyloid bundles. This study highlights the potential role of future immunotherapies in treating Alzheimer’s disease.

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LILRB4 is an inhibitory receptor on microglia that weakens their activation. The research team led by Dr. Marco Colonna found that this receptor is highly present in the microglia that surround the amyloid plaque bundles in the brains of early and late-stage Alzheimer’s patients.

To uncover the role of LILRB4 in Alzheimer’s, the scientists introduced the human version of the receptor into mice that overproduce amyloid plaques. As with Alzheimer’s patients, the researchers found that with increasing amyloid plaque in Alzheimer’s mice, so did human LILRB4 on the mice’s microglia.

To understand if blocking LILRB4 signaling could reduce amyloid plaques in the Alzheimer’s mice, a monoclonal antibody against LILRB4 was developed. When administered intravenously, the antibody successfully crosses the blood-brain barrier and reaches the brain. Researchers administered eight weekly injections of the novel antibody and evaluated the mice for levels of amyloid pathology as well as behavioral assessments.

The treatment changed some behaviors in the mice linked to amyloid beta accumulation and Alzheimer’s disease pathology. Specifically, the mice exhibited fewer risk-taking behaviors, often associated with Alzheimer’s patients who exhibit impaired memory. The treatment also resulted in approximately a 50% reduction in total plaques, including reductions in regions particularly important for learning and memory, the cortex, and hippocampus. The researchers evaluated the potential damage from the antibody to the blood-brain barrier and determined there were no clear signs of microbleeds.

Further investigation revealed that the anti-LILRB4 antibody increased microglial activation and the clearance of amyloid beta while also reducing proinflammatory signaling.

The LILRB4 receptor does not directly bind to amyloid beta in plaques. The LILRB4 receptor’s inhibitory effects are mediated through its interaction with the APOE protein found in plaques. Thus, APOE is the binding agent for the inhibitory receptor that diminishes microglial overall clearance abilities. The antibody competes with APOE for binding to LILRB4, preventing APOE from slowing down microglia’s ability to clear amyloid plaques.

The recent discovery of LILRB4’s role in microglial clearance contributes to the growing evidence that adjusting microglial activity could be beneficial in treating Alzheimer’s. The study demonstrates that an antibody targeting LILRB4 can enhance microglia’s capacity to remove amyloid plaques and decrease inflammation. Consequently, LILRB4 represents a potential target for drug intervention and offers new ways to support the protective functions of microglia for Alzheimer’s treatment.

Published in Science Translational Medicine

Marco Colonna, M.D., Washington University School of Medicine in St. Louis

David M. Holtzman, M.D.,  Washington University School of Medicine in St. Louis

Antibody-mediated targeting of human microglial leukocyte Ig-like receptor B4 attenuates amyloid pathology in a mouse model