Enabling Microglia to Better Clear Amyloid by Interfering in the LILRB4-APOE Interaction

Researchers here describe a mechanism that reduces the ability of microglia to ingest and clear misfolded amyloid-β, the protein aggregates associated with Alzheimer's disease. Interestingly, this involves APOE, and thus might be affected by the different APOE variants connected to Alzheimer's disease risk. The researchers demonstrate that interfering in the interaction between APOE and the LILRB4 receptor present on microglia can restore microglia-mediated clearance of amyloid-β.

Toxic clumps of brain proteins are features of many neurodegenerative conditions, including Alzheimer's disease (AD), Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Microglia surround plaques to create a barrier that controls the damaging protein's spread. They also can engulf and destroy the plaque proteins, but in Alzheimer's disease they usually do not. The source of their passivity could result from a protein called APOE that is a component of amyloid plaques. The APOE proteins in the plaque bind to a receptor - LILRB4 - on the microglia surrounding the plaques, inactivating them.

For reasons that are still unknown, the researchers found that, in mice and people with Alzheimer's disease, microglia that surround plaques produce and position LILRB4 on their cell surface, which inhibits their ability to control damaging plaque formation upon binding to APOE. Researchers treated mice that had amyloid beta plaques in the brain with a homemade antibody that blocked APOE from binding to LILRB4. The researchers found that activated microglia were able to engulf and clear the amyloid beta plaques.

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

Link: https://medicine.wustl.edu/news/immunotherapy-for-alzheimers-disease-shows-promise-in-mouse-study/