APOE4 is a strong risk factor for Alzheimer’s disease (AD) and, when expressed on ‘neurodegenerative microglia’ (MGnDs), it impairs the neuroprotective function of these cells. A study published in Nature Medicine now shows that MGnDs interact with a subset of immunosuppressive IL-17-producing neutrophils. Extensive transcriptomics analyses showed that IL-17 signaling is increased in neutrophils from cognitively impaired and older individuals, and in female APOE4 carriers in particular. In brain samples from APOE4 carriers with AD, infiltrating APOE-expressing neutrophils appeared to interact with microglia at plaque sites; IL-17F–IL-17RA interactions between neutrophils and microglia were upregulated in female APOE4 carriers. Experiments in transgenic mouse models of AD indicated that deleting APOE4 expression from neutrophils reduces their IL-17 signaling, increases the transcriptional signature of MGnDs, reduces plaques and restores Y-maze performance. Preventing IL-17F signaling in microglia had similar effects and decreased the recruitment of neutrophils. Together, these findings point to a mechanism by which APOE4 increases the risk of AD pathology in women. Further research may establish whether targeting IL-17 might be beneficial in female APOE4 carriers.

Original reference: Nat. Med. https://doi.org/10.1038/s41591-024-03122-3 (2024)