Sex-dependent APOE4 neutrophil-microglia interactions drive cognitive impairment in Alzheimer's disease.
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.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Microglía
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Apolipoproteína E4
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Enfermedad de Alzheimer
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Disfunción Cognitiva
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Neutrófilos
Límite:
Aged
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Animals
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Female
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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