Alzheimer’s disease is characterized by the buildup of a sticky protein called amyloid beta in the brain, leading to the formation of plaques that cause brain atrophy and cognitive decline. The latest generation of Alzheimer’s drugs focuses on tagging amyloid for clearance by the brain’s immune cells. Researchers at Washington University School of Medicine in St. Louis have now discovered a new method to remove these plaques by activating immune cells called microglia to consume them. This approach has shown promise in reducing amyloid plaques and improving behavioral abnormalities in mice with Alzheimer’s-like disease.
The implications of this new method extend beyond Alzheimer’s disease, as toxic clumps of proteins in the brain are also present in other neurodegenerative conditions such as Parkinson’s disease, ALS, and Huntington’s disease. By activating microglia with an antibody, researchers were able to remove amyloid beta plaques in mice, indicating the potential for this approach to clear other harmful proteins in various neurodegenerative diseases. This method of immunotherapy, which harnesses the immune system to remove damaging proteins from the brain, could be a significant advancement in the treatment of these conditions.
In Alzheimer’s disease, microglia surround plaques to create a barrier that controls the spread of the damaging proteins. However, they typically do not engulf and destroy the plaque proteins. The passivity of microglia may be due to the binding of APOE proteins in the plaques to a receptor called LILRB4 on the microglia, inhibiting their ability to control plaque formation. By blocking the binding of APOE to LILRB4 with an antibody, researchers were able to activate microglia to engulf and clear the amyloid beta plaques in mice.
Clearing amyloid beta plaques not only reduces the pathology in the brain but also has a positive impact on behavior. In individuals with AD, the lack of memory of past experiences can lead to risky behavior, making them vulnerable to exploitation. Treatment with an antibody to clear plaques showed promise in altering risk-taking behavior in mice. Additionally, the researchers plan to test the antibody in mice with tau tangles, which represent a later stage of the disease where neurons die, and cognitive symptoms arise.
While drugs targeting amyloid plaques directly have been successful in modifying the course of Alzheimer’s disease, they can also induce potentially serious side effects. For example, removing plaques from brain blood vessels can lead to swelling and bleeding, known as ARIA. The researchers are working with a mouse model that has plaques on brain arteries to understand the risk of ARIA associated with their new approach. By exploring different methods of removing harmful proteins from the brain, researchers hope to develop more effective and safer treatments for neurodegenerative diseases like Alzheimer’s.
