APOE4 impairs Microglia ‐ Astrocyte Crosstalk in Alzheimer Disease

Abstract Background APOE4 is the major genetic risk factor for late‐onset Alzheimer Disease (AD). APOE signaling is critical for the transition of homeostatic microglia to the neurodegenerative phenotype (MGnD). The intrinsic role of APOE4 in microglia and its contribution to AD is unclear. Method Generation of Cx3cr1‐CRE ERT2 mice crossed to APOE‐KI(APOE3 and APOE4) fl/fl injected with labeled apoptotic neurons (MGnD‐Pardigm) on WT or APP/PS1 background. Microglia and astrocytes were isolated and sequenced using either bulk RNA‐seq (MGnD‐Paradigm) or single‐cell RNA‐seq (APP/PS1). Crosstalk between cells was determined using the NichenetR database and validated using 1) Recombinant Lgals3 intracranial injection into APP/PS1 mice and 2) Adoptive transfer of microglia, from APOE3‐KI, APOE4‐KI and APOE4‐cKO mice challenged with labeled apoptotic neurons, into WT mice and isolation of astrocytes. Result Expression of APOE4 in microglia impaired MGnD‐transition in response to neurodegeneration and in APP/PS1 mice. Conditional deletion of APOE4 in microglia restored MGnD phenotype and reduced plaque pathology. Furthermore, increased astrocytic recruitment towards plaques and their activation by increased Gfap and Serpina3n expression was identified. Microglial Lgals3 was determined as critical crosstalk effector to promote astrocyte response to plaque pathology and acute neurodegeneration. AD female APOE4 carriers showed impaired induction of MGnD signature genes and astrocyte activation, including LGALS3 and GFAP respectively, supporting a conserved disease mechanism in a sex‐dependent manner. Conclusion APOE4 impairs MGnD‐microglia in AD and prevents their crosstalk with astrocytes. Lgals3 is identified as important positive regulator for microglia–astrocyte crosstalk in response to AD pathology and provides a potential therapeutic target for treatment of AD.