APOE4 Regulation of Neutrophil-Microglia Cross-Talk in Alzheimer’s Disease

Project Summary

Our proposal is based on conceptual innovation: 1) APOE4 drives a gender-dependent inflammatory signature in neutrophils. 2) APOE4-mediated recruitment of neutrophils in AD mice. 3) APOE4 neutrophils associated with neurodegenerative microglial signature. Technical innovation: i) identification and generation of microglia- and monocyte-specific mAbs; ii) spatial characterization of immune subsets utilizing MERFISH; iii) new genetic mouse model to delete human ApoE variants in neutrophils. These strategies will allow us to investigate the role of ApoE in neutrophils-microglia crosstalk in AD.APOE4 is the strongest genetic risk factor for AD, however the interactions between APOE4, innate immunity and their contribution to AD, are unknown. Successful completion of this project can provide new mechanisms of APOE4 in the regulation of neutrophil-microglia crosstalk and their impact in neurodegeneration. Importantly, targeting neutrophils-microglia axis is feasible and clinically applicable. Thus, the proposed project is of immense relevance due to its possible contribution both for basic science of APOE and AD, and may have significant input for future immunotherapies for AD.