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Sex-dependent APOE4 neutrophil-microglia interactions drive cognitive impairment in Alzheimer's disease.
Rosenzweig, Neta; Kleemann, Kilian L; Rust, Thomas; Carpenter, Madison; Grucci, Madeline; Aronchik, Michael; Brouwer, Nieske; Valenbreder, Isabel; Cooper-Hohn, Joya; Iyer, Malvika; Krishnan, Rajesh K; Sivanathan, Kisha N; Brandão, Wesley; Yahya, Taha; Durao, Ana; Yin, Zhuoran; Chadarevian, Jean Paul; Properzi, Michael J; Nowarski, Roni; Davtyan, Hayk; Weiner, Howard L; Blurton-Jones, Mathew; Yang, Hyun-Sik; Eggen, Bart J L; Sperling, Reisa A; Butovsky, Oleg.
Afiliación
  • Rosenzweig N; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • Kleemann KL; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • Rust T; Institute for Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany.
  • Carpenter M; Department of Biomedical Sciences, Section Molecular Neurobiology, University Medical Center Groningen, Groningen, The Netherlands.
  • Grucci M; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • Aronchik M; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • Brouwer N; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • Valenbreder I; Department of Biomedical Sciences, Section Molecular Neurobiology, University Medical Center Groningen, Groningen, The Netherlands.
  • Cooper-Hohn J; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • Iyer M; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • Krishnan RK; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • Sivanathan KN; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • Brandão W; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • Yahya T; Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Mass General Hospital and Harvard Medical School, Boston, MA, USA.
  • Durao A; Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
  • Yin Z; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • Chadarevian JP; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • Properzi MJ; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • Nowarski R; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • Davtyan H; Department of Neurobiology & Behavior, University of California, Irvine, Irvine, CA, USA.
  • Weiner HL; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA, USA.
  • Blurton-Jones M; Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA, USA.
  • Yang HS; Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • Eggen BJL; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • Sperling RA; Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Mass General Hospital and Harvard Medical School, Boston, MA, USA.
  • Butovsky O; Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
Nat Med ; 30(10): 2990-3003, 2024 Oct.
Article en En | MEDLINE | ID: mdl-38961225
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 TGFß 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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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Microglía / Apolipoproteína E4 / Enfermedad de Alzheimer / Disfunción Cognitiva / Neutrófilos Límite: Aged / Animals / Female / Humans / Male Idioma: En Revista: Nat Med Asunto de la revista: BIOLOGIA MOLECULAR / MEDICINA Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Microglía / Apolipoproteína E4 / Enfermedad de Alzheimer / Disfunción Cognitiva / Neutrófilos Límite: Aged / Animals / Female / Humans / Male Idioma: En Revista: Nat Med Asunto de la revista: BIOLOGIA MOLECULAR / MEDICINA Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos