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| Status |
Public on Jun 04, 2024 |
| Title |
Sex-dependent APOE4 Neutrophil-microglia interactions drive cognitive impairment in Alzheimer's Disease |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
APOE4 is the strongest genetic risk factor for Alzheimer's disease (AD) with increased odds ratios in females. Targeting amyloid plaques show 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 AD patients, we identify a new subset of neutrophils, interacting with microglia associated with cognitive impairment. This phenotype is defined by increased IL-17 and IL-1 co-expressed gene modules in blood neutrophils and in microglia of cognitively impaired female APOE e4 carriers, showing increased infiltration to the AD brain. APOE4 female IL-17+ neutrophils upregulated the immunosuppressive cytokines IL-10 and TGFb, and immune checkpoints including LAG-3 and PD-1, associated with accelerated immune aging. Deletion of APOE4 in neutrophils reduced this immunosuppressive phenotype and restored microglial response to neurodegeneration (MGnD), limiting plaque pathology in AD mice. Mechanistically, IL-17F upregulated in APOE4 neutrophils interacts with microglial IL-17RA to suppress the induction of MGnD phenotype, and blocking this axis supported cognitive improvement in AD mice. These findings provide a translational basis to target IL-17F in APOE e4 female carriers with cognitive impairment.
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| Overall design |
Splenic neutrophils were collected from 9-month-old APOE4 5xFAD mice treated with IL17F or IgG.Neutrophils were collected from the blood of 12-month-old female APOE3, APOE3NTKO, APOE4 and APOE4NTKO mice on an APP/PS1 background. Phagocytic and non-phagocytic microglia were collected from3-month-old Raggc mice treated with anti-IL17F or IgG.
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| Contributor(s) |
Rosenzweig N, Kleemann KL, Rust T, Carpenter M, Grucci M, Aronchik M, Brouwer N, Valenbreder I, Cooper-Hohn J, Iyer M, Krishnan RK, Sivanathan K, Brandão W, Yahya T, Durao A, Chadarevian J, Yin Z, Properzi M, Nowarski R, Davtyan H, Blurton-Jones M, Yang H, Eggen BJ, Sperling R, Butovsky O |
| Citation(s) |
38961225 |
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| Submission date |
Mar 27, 2024 |
| Last update date |
Sep 09, 2024 |
| Contact name |
Neta Rosenzweig |
| E-mail(s) |
NROSENZWEIG@BWH.HARVARD.EDU
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| Organization name |
Brigham and Women's Hospital, Harvard Medical School
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| Street address |
60 Fenwood Road, 10002K, Brigham and Women’s Hospital
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| City |
Boston |
| State/province |
Massachusetts |
| ZIP/Postal code |
02115 |
| Country |
USA |
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| Platforms (1) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
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| Samples (39)
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| This SubSeries is part of SuperSeries: |
| GSE243750 |
SEX-DEPENDENT APOE4 NEUTROPHIL-MICROGLIA INTERACTIONS DRIVE COGNITIVE IMPAIRMENT IN ALZHEIMER'S DISEASE |
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| Relations |
| BioProject |
PRJNA1092673 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE262632_RAW.tar |
51.6 Mb |
(http)(custom) |
TAR (of SF) |
SRA Run Selector |
| Raw data are available in SRA |
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