APOE4 Regulation of Neutrophil-Microglia Cross-Talk in Alzheimer’s Disease
This proposal aims to investigate the underlying mechanism of APOE4 in the regulation of neutrophil-microglia crosstalk in Alzheimer’s disease.Aim 1: Define the role of APOE variants in neutrophils and their impact on microglia regulation in AD mice. We will 1) determine how APOE variants in neutrophils affects their regulation and 2) investigate the impact of neutrophilic APOE variant deletion on microglia phenotypes and disease progression. Aim 2: Define the role of APOE variants in human neutrophils and their impact on human microglia in AD. We will 1) characterize neutrophils isolated from APOE E2, E3, and E4 donors and 2) determine the effect of APOE variants in human neutrophils and their crosstalk with human microglia.
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.