2. Academic Validation
  3. Sex-dependent APOE4 neutrophil-microglia interactions drive cognitive impairment in Alzheimer's disease

Sex-dependent APOE4 neutrophil-microglia interactions drive cognitive impairment in Alzheimer's disease

  • Nat Med. 2024 Oct;30(10):2990-3003. doi: 10.1038/s41591-024-03122-3.
Neta Rosenzweig # 1,  Kilian L Kleemann # 1 2,  Thomas Rust # 3,  Madison Carpenter 1,  Madeline Grucci 1,  Michael Aronchik 1,  Nieske Brouwer 3,  Isabel Valenbreder 1,  Joya Cooper-Hohn 1,  Malvika Iyer 1,  Rajesh K Krishnan 1,  Kisha N Sivanathan 1 4 5,  Wesley Brandão 1,  Taha Yahya 1,  Ana Durao 1,  Zhuoran Yin 1,  Jean Paul Chadarevian 6 7 8,  Michael J Properzi 9,  Roni Nowarski 1 4 5,  Hayk Davtyan 6 7 8,  Howard L Weiner 1 4 10,  Mathew Blurton-Jones 6 7 8,  Hyun-Sik Yang 9 10,  Bart J L Eggen 3,  Reisa A Sperling 9 10,  Oleg Butovsky 11 12
Affiliations

Affiliations

  • 1 Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • 2 Institute for Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany.
  • 3 Department of Biomedical Sciences, Section Molecular Neurobiology, University Medical Center Groningen, Groningen, The Netherlands.
  • 4 Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Mass General Hospital and Harvard Medical School, Boston, MA, USA.
  • 5 Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
  • 6 Department of Neurobiology & Behavior, University of California, Irvine, Irvine, CA, USA.
  • 7 Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA, USA.
  • 8 Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA, USA.
  • 9 Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • 10 Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • 11 Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. obutovsky@bwh.harvard.edu.
  • 12 Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Mass General Hospital and Harvard Medical School, Boston, MA, USA. obutovsky@bwh.harvard.edu.
  • # Contributed equally.
PMID: 38961225 DOI: 10.1038/s41591-024-03122-3
Abstract

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 ε4 carriers, showing increased infiltration to the AD brain. APOE4 female IL-17+ neutrophils upregulated the immunosuppressive cytokines IL-10 and TGFβ 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 ε4 female carriers with cognitive impairment.

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