International Business Department           Liu Bojia           April 9, 2023

  As the most common neurodegenerative disease, Alzheimer's disease can severely impair memory, thinking ability, and may eventually lead to death. A classic symptom of Alzheimer's disease is beta amyloid plaques, a build-up of beta amyloid in the brain that leads to neurotangles that are strongly associated with brain atrophy as well as cognitive decline.

  In 2023, lecanemab, the first new Alzheimer's disease drug in nearly 20 years to be fully approved by the FDA, succeeded in altering the course of Alzheimer's disease precisely through the therapeutic effect of an antibody that binds specifically to beta amyloid.

  Now, in a Science Translational Medicine paper, a team of researchers from Washington University in St. Louis has demonstrated a new strategy for clearing toxic protein plaques: by restoring the protein-cleansing capacity of immune cells of the nervous system through antibodies, they directly mobilise their own microglia to reduce amyloid depos its. In mouse experiments, this new immunotherapy was successful in reducing toxic plaques and attenuating behavioural abnormalities in Alzheimer's disease-like mice, making it a highly promising potential therapy.

  Microglia are the most important class of immune cells in the central nervous system, which normally form a barrier around amyloid plaques to control the spread of harmful proteins, and can also engulf and destroy these protein plaques.

  In Alzheimer's disease, however, the ability of microglia to clear plaques is significantly diminished, and this difference may be related to the ApoE protein. As a component of amyloid plaques, the ApoE protein is able to bind to the leukocyte immunoglobulin-like receptor LILRB4 on microglia surrounding plaques, inhibiting microglia activity.

  Examining brain tissue sections from patients with Alzheimer's disease, the team found that the patients had a large number of LILRB4 receptors on the surface of their microglia; using a transgenic mouse model that expresses the human LILRB4 receptor, the team further confirmed this finding and demonstrated that LILRB4 inhibits the ability of microglia to clear β-amyloid plaques.

  The above findings also point to potential routes for treatment. The research team designed a monoclonal antibody against human LILRB4 and treated a mouse model with beta amyloid plaques in the brain and found that the antibody blocked the binding of ApoE to LILRB4 and enhanced the activity of microglia. These activated microglia were also effective in reducing plaques in the mice's brains.

  The use of the brand new antibody also caused behavioural changes in behavioural tests, mitigating risk-taking behaviour in the mice. People with Alzheimer's disease tend to lack memory of past experiences and therefore may engage in risk-taking behaviour, such as being more susceptible to deception. Antibody treatments used to remove protein plaques, on the other hand, have shown the potential to change behaviour.

  Notably, drugs that directly target amyloid plaques can cause potentially serious side effects. In patients with Alzheimer's disease, beta amyloid builds up in the walls of the brain's arteries as well as in other parts of the brain tissue. If the plaque is removed from the blood vessels in the brain, it may cause swelling and bleeding, a side effect known as amyloid-related imaging abnormalities (ARIA). The mice used in this study lacked amyloid plaque on their blood vessels, so the researchers have not yet been able to assess whether this side effect exists. They are currently testing this risk in a mouse model with plaque on brain arteries.

  "Lecanemab, as the first therapeutic antibody capable of altering the course of the disease, confirms the importance of beta amyloid in the progression of Alzheimer's disease," said Professor David Holtzman, an author of the paper, "and it opens up new opportunities for the development of other immunotherapies, the These therapies use different approaches to remove harmful proteins from the brain."

  The team noted that since toxic protein plaques are not only associated with Alzheimer's disease, but are also characteristic of a number of neurodegenerative diseases such as Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease, this immunotherapy could have far-reaching implications for the treatment of a wider range of neurodegenerative diseases. The research team is also currently exploring other potential immunotherapies to remove harmful proteins that may promote other diseases.