Apolipoprotein E4 (APOE4) is associated with greatly elevated risks for Alzheimer’s disease (AD) compared to APOE2, which differs from APOE4 by only two amino acids. The underlying mechanism remains enigmatic. The research groups of Drs. Yigong Shi and Jiayao Zhou, from Westlake University, have demonstrated that APOE4, but not APOE2, specifically interacts with the cell surface leukocyte immunoglobulin-like receptor B3 (LilrB3). APOE4, but not APOE2, activates human microglia cells into a pro-inflammatory state, which is associated with increased synapse pruning and neurotoxic cytokine release. The APOE4-dependent activation of microglia strictly depends on LilrB3, as its ablation leads to abrogation of such activation. The atomic structure of the ligand-receptor complex reveals how the N-terminal domain (NTD) of APOE4 binds the extracellular domain (ECD) of LilrB3, triggering its dimerization and potential activation. Together, they identify LilrB3 as a putative cell surface receptor for APOE4 and may explain why APOE4, but not APOE2, contributes to the high risks of AD. Finally, they provide evidence that blocking APOE4 binding to LilrB3 may constitute a potential strategy for therapeutic intervention of AD.

The research was published inCell Researchin Jan , 2023 and selected as the cover story.