| First Author | Rosenzweig N | Year | 2024 |
| Journal | Nat Med | Volume | 30 |
| Issue | 10 | Pages | 2990-3003 |
| PubMed ID | 38961225 | Mgi Jnum | J:359458 |
| Mgi Id | MGI:7787166 | Doi | 10.1038/s41591-024-03122-3 |
| Citation | Rosenzweig N, et al. (2024) Sex-dependent APOE4 neutrophil-microglia interactions drive cognitive impairment in Alzheimer's disease. Nat Med 30(10):2990-3003 |
| abstractText | APOE4 is the strongest genetic risk factor for Alzheimer's disease (AD), with increased odds ratios in female carriers. Targeting amyloid plaques shows modest improvement in male non-APOE4 carriers. Leveraging single-cell transcriptomics across APOE variants in both sexes, multiplex flow cytometry and validation in two independent cohorts of APOE4 female carriers with AD, we identify a new subset of neutrophils interacting with microglia associated with cognitive impairment. This phenotype is defined by increased interleukin (IL)-17 and IL-1 coexpressed gene modules in blood neutrophils and in microglia of cognitively impaired female APOE epsilon4 carriers, showing increased infiltration to the AD brain. APOE4 female IL-17(+) neutrophils upregulated the immunosuppressive cytokines IL-10 and TGFbeta and immune checkpoints, including LAG3 and PD-1, associated with accelerated immune aging. Deletion of APOE4 in neutrophils reduced this immunosuppressive phenotype and restored the microglial response to neurodegeneration, limiting plaque pathology in AD mice. Mechanistically, IL-17F upregulated in APOE4 neutrophils interacts with microglial IL-17RA to suppress the induction of the neurodegenerative phenotype, and blocking this axis supported cognitive improvement in AD mice. These findings provide a translational basis to target IL-17F in APOE epsilon4 female carriers with cognitive impairment. |
