Immunotherapy for Alzheimer’s Disease Shows Promising Results in a Mouse Study

Alzheimer’s disease begins with a sticky protein called beta-amyloid, which builds up into plaques in the brain and sets off a chain of events that lead to brain shrinkage and cognitive decline. The new generation of Alzheimer’s drugs – the first that have been shown to alter the course of the disease – work by marking amyloid for clearance by the brain’s immune cells. Scientists have shown that treating mice with an antibody that blocks the interaction between APOE proteins (white), which are scattered in Alzheimer’s plaques, and the LILRB4 receptor on microglial cells (purple), stimulates them to clear harmful plaques (blue) in the brain.

Immune Cells that Remove Plaque to Counteract Alzheimer’s Disease

Now, researchers at Washington University School of Medicine in St. Louis have found a different and promising way to remove the harmful plaques: they directly mobilize immune cells that eat them up. In a study published in the journal Science Translational Medicine, the researchers showed that activating immune cells called microglia with an antibody reduced amyloid plaques in the brain and alleviated behavioral abnormalities in mice with Alzheimer’s-like disease.

The approach could have implications beyond Alzheimer’s disease. Toxic clumps of brain proteins are hallmarks of many neurodegenerative diseases, including Parkinson’s disease, amyotrophic lateral sclerosis (ALS) and Huntington’s disease. Encouraged by the study results, researchers are exploring other potential immunotherapies – drugs that use the immune system – to remove junk proteins from the brain that are thought to promote other diseases.

By generally activating microglia, the antibody can remove beta-amyloid plaques in mice, according to the study’s lead author, Dr. Marco Colonna, professor of pathology at Robert Rock Belliveau University, and it could potentially clear other harmful proteins in additional neurodegenerative diseases, including Parkinson’s disease.

Removal of Plaques in Mice Also Reduces Risk Propensity

Microglia surround the plaques and form a barrier that controls the spread of the harmful protein. They can also engulf and destroy the plaque proteins, but in Alzheimer’s disease they do not normally do so. The reason for their passivity may lie in a protein called APOE, which is a component of amyloid plaques. The APOE proteins in the plaques bind to a receptor – LILRB4 – on the microglia surrounding the plaques and inactivate them.

For reasons still unknown, the researchers found that in mice and humans with Alzheimer’s disease, the microglia surrounding the plaques produce and position LILRB4 on their cell surface, which inhibits their ability to control harmful plaque formation after binding to APOE. The other first author, Jinchao Hou, PhD, now a faculty member at Children’s Hospital of Zhejiang University School of Medicine in Zhejiang Province, China, treated mice with amyloid beta plaques in the brain with a home-made antibody that blocked the binding of APOE to LILRB4. After collaborating with Dr. Yongjian Liu, professor of radiology at the University of Washington’s Mallinckrodt Institute of Radiology, to confirm that the antibody reached the brain, the researchers found that activated microglia were able to engulf and remove the amyloid beta plaques.

The removal of beta-amyloid plaques in mice also reduces risk taking. People with Alzheimer’s can no longer remember past experiences to make decisions. They may engage in risky behavior, making them vulnerable to becoming victims of fraud or financial abuse. Treating mice with an antibody to remove the plaques showed a promising change in behavior.

After amyloid beta plaques form in the brain, another brain protein – tau – becomes tangled up in the neurons. In this second stage of the disease, neurons die and cognitive symptoms appear. High levels of LILRB4 and APOE have been observed in AD patients at this later stage. It is possible that blocking the interaction between the proteins and activating the microglia could alter the later stages of the disease. In future studies, the researchers will test the antibody on mice with tau tangles.

Development of Other Immunotherapies

Drugs that directly target amyloid plaques can have a potentially serious side effect. In Alzheimer’s patients, amyloid proteins build up on the walls of arteries in the brain as well as other parts of brain tissue. The removal of plaques from the blood vessels of the brain can lead to swelling and bleeding, a side effect known as ARIA. This side effect occurs in some patients receiving lecanemab, a drug approved by the Food and Drug Administration for the treatment of Alzheimer’s disease.

The mice used in this study did not have amyloid plaques on the blood vessels, so the researchers could not assess what happens when the plaques on the blood vessels are removed. They are working with a different mouse model – one that has plaques on the brain arteries – to see if this new approach also carries a risk for ARIA. Lecanemab, the first therapeutic antibody to alter disease progression, confirmed the importance of the amyloid beta protein in the progression of Alzheimer’s disease. And it opened up new possibilities for the development of other immunotherapies that use different methods to remove harmful proteins from the brain.