Alzheimer’s disease is the most common form of dementia and is related to the buildup of a protein called amyloid beta that forms plaques in the brain and causes brain atrophy and cognitive decline. The new generation of drugs against Alzheimer’s – the first that have been shown to change the course of the disease – act by marking amyloid for elimination by immune cells in the brain.
Now, researchers at Washington University School of Medicine in St. Louis have discovered a different and promising way to remove these harmful plaques: directly mobilizing immune cells to consume them. These experts have shown that activating immune cells called microglia with an antibody reduces amyloid plaques in the brain and attenuates behavioral abnormalities in mice with an Alzheimer’s-like disease.
This approach could have implications beyond Alzheimer’s, as toxic clumps of brain proteins are characteristic of many neurodegenerative pathologies, including Parkinson’s disease, amyotrophic lateral sclerosis (ALS), and Huntington’s disease. The research has been published in Science Translational Medicine.
Motivated by the results, researchers are exploring other potential immunotherapies, drugs that harness the immune system to eliminate harmful proteins in the brain that are believed to contribute to the progression of other diseases. “By generally activating microglia, our antibody can eliminate amyloid beta plaques in mice, and potentially clear other harmful proteins in different neurodegenerative diseases, including Parkinson’s disease,” explained the study’s lead author, Dr. Marco. Colonna, Robert Rock Belliveau Professor of Pathology.
Destroy brain-damaging plaques without causing side effects
Microglia surround the plaques, forming a barrier that limits the dispersion of the harmful protein. They can also engulf and destroy plaque proteins, but in Alzheimer’s disease they usually do not. The origin of its passivity could be the responsibility of a protein called APOE, which is a component of amyloid plaques. APOE proteins in the plaque bind to a receptor – LILRB4 – on the microglia surrounding the plaques, deactivating them, explained Yun Chen, co-senior author of the study.
For reasons still unknown, the researchers found that, in both mice and people with Alzheimer’s disease, microglia surrounding plaques produce and position LILRB4 on their cell surface, inhibiting their ability to control the formation of harmful plaques by binding to APOE.
Jinchao Hou, another co-lead author, treated mice that had amyloid beta plaques in the brain with a homemade antibody that blocked APOE binding to LILRB4. After working with Yongjian Liu, a professor of radiology at the Mallinckrodt Institute of Radiology at the University of Washington, to confirm that the antibody reached the brain, the researchers found that activated microglia were able to engulf and remove amyloid beta plaques.
Removing amyloid beta plaques in mice also reduces risk-taking behavior. Individuals with Alzheimer’s may lack memory of past experiences to help them make decisions and engage in risky behavior, making them vulnerable to becoming victims of fraud or financial abuse. Treating the mice with an antibody to remove plaques showed promise in modifying their behavior.
“By activating microglia, our antibody can eliminate amyloid beta plaques in mice, and potentially clean up other harmful proteins in other neurodegenerative diseases, such as Parkinson’s”
After amyloid beta plaques form in the brain, another brain protein – tau – tangles inside neurons. In this second stage of the disease, neurons die and cognitive symptoms arise. Chen explained that high levels of LILRB4 and APOE have been observed in Alzheimer’s patients at this later stage. It is possible that blocking protein interaction and activating microglia could alter the later stages of the disease. In future studies, the researchers will test the antibody in mice with tau tangles.
Drugs that directly target amyloid plaques can cause a potentially serious side effect. In patients with Alzheimer’s, amyloid proteins also accumulate in the walls of the arteries of the brain, as well as in other parts of the brain tissue. Removing plaques from brain blood vessels can induce swelling and bleeding, a side effect known as ARIA. This side effect has been seen in some patients receiving lecanemab, a drug approved by the FDA to treat Alzheimer’s.
The mice used in this study lacked amyloid plaques in blood vessels, so the researchers could not evaluate what happens when plaques are removed from blood vessels. So they are now working with a different mouse model – one that does have plaques in the brain arteries – to find out if this new approach also carries a risk of ARIA.
“Lecanemab, as the first therapeutic antibody that has been able to modify the course of the disease, confirmed the importance of amyloid beta protein in the progression of Alzheimer’s disease,” said Dr. David Holtzman, Barbara Burton and Reuben M Distinguished Professor. Morriss III of Neurology and author of the work. “And it has opened new opportunities to develop other immunotherapies that use different methods to eliminate harmful proteins from the brain,” he concludes.
