TY - JOUR
T1 - Sex-dependent APOE4 neutrophil–microglia interactions drive cognitive impairment in Alzheimer’s disease
AU - Rosenzweig, Neta
AU - Kleemann, Kilian L.
AU - Rust, Thomas
AU - Carpenter, Madison
AU - Grucci, Madeline
AU - Aronchik, Michael
AU - Brouwer, Nieske
AU - Valenbreder, Isabel
AU - Cooper-Hohn, Joya
AU - Iyer, Malvika
AU - Krishnan, Rajesh K.
AU - Sivanathan, Kisha N.
AU - Brandão, Wesley
AU - Yahya, Taha
AU - Durao, Ana
AU - Yin, Zhuoran
AU - Chadarevian, Jean Paul
AU - Properzi, Michael J.
AU - Nowarski, Roni
AU - Davtyan, Hayk
AU - Weiner, Howard L.
AU - Blurton-Jones, Mathew
AU - Yang, Hyun Sik
AU - Eggen, Bart J.L.
AU - Sperling, Reisa A.
AU - Butovsky, Oleg
N1 - Publisher Copyright:
© The Author(s), under exclusive licence to Springer Nature America, Inc. 2024.
PY - 2024/10
Y1 - 2024/10
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85197865950
U2 - 10.1038/s41591-024-03122-3
DO - 10.1038/s41591-024-03122-3
M3 - Article
AN - SCOPUS:85197865950
SN - 1078-8956
VL - 30
SP - 2990
EP - 3003
JO - Nature Medicine
JF - Nature Medicine
ER -