Sex-dependent APOE4 Neutrophil-microglia Interactions Drive Cognitive Impairment in Alzheimer's Disease

Overview

Journal Nat Med

Specialties General Medicine
Molecular Biology

Date 2024 Jul 3

PMID 38961225

Authors

Neta Rosenzweig

Kilian L Kleemann

Thomas Rust

Madison Carpenter

Madeline Grucci

Michael Aronchik

Nieske Brouwer

Isabel Valenbreder

Joya Cooper-Hohn

Malvika Iyer

Rajesh K Krishnan

Kisha N Sivanathan

Wesley Brandao

Taha Yahya

Ana Durao

Zhuoran Yin

Jean Paul Chadarevian

Michael J Properzi

Roni Nowarski

Hayk Davtyan

Howard L Weiner

Mathew Blurton-Jones

Hyun-Sik Yang

Bart J L Eggen

Reisa A Sperling

Oleg Butovsky

Affiliations

Soon will be listed here.

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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