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
  • 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. [email protected].
  • 12. Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Mass General Hospital and Harvard Medical School, Boston, MA, USA. [email protected].
  • # 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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