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SEX-DEPENDENT APOE4 NEUTROPHIL-MICROGLIA INTERACTIONS DRIVE COGNITIVE IMPAIRMENT IN ALZHEIMER'S DISEASE [Microglia_IL17RA]

ABSTRACT: APOE4 is the strongest genetic risk factor for Alzheimer's disease (AD) with increased odds ratios in females. Targeting amyloid plaques show modest improvement in male non-APOE4 carriers. Leveraging transcriptomics across APOE variants in both sexes, multiplex flow cytometry and validation in two independent cohorts of APOE4 female AD patients, we identify a new subset of neutrophils associated with cognitive impairment. This phenotype is defined by increased IL-17 and IL-1 co-expressed gene modules in blood neutrophils of cognitively impaired female APOE e4 carriers, showing increased infiltration to the AD brain. APOE4 female IL-17+ neutrophils upregulated the immunosuppressive cytokines IL-10 and TGFb, and immune checkpoints including LAG-3 and PD-1, associated with accelerated immune aging. Deletion of APOE4 in neutrophils reduced this immunosuppressive phenotype and restored microglial response to neurodegeneration (MGnD), limiting plaque pathology in AD mice. Mechanistically, IL-17Fupregulated in APOE4 neutrophils interacts with microglial IL-17RA to suppress the induction of MGnD phenotype, and blocking this axis supported cognitive improvement in AD mice. These findings provide a translational basis to target IL-17F in APOE e4 female carriers with cognitive impairment.

ORGANISM(S): Mus musculus

PROVIDER: GSE243746 | GEO | 2024/06/04

REPOSITORIES: GEO

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Project description:Cerebrovascular dysfunction is a hallmark feature of Alzheimer's disease (AD). One of the greatest risk factor for AD is the apolipoprotein E4 (E4) allele. APOE4 genotype has been shown to negatively impact on perivascular amyloid clearance, however, its direct influence along with the other APOE variants (APOE2 and APOE3) on the molecular integrity of the cerebrovasculature has not been largely explored. To address this, we employed a 10-plex tandem isobaric mass tag approach in combination with an ultra-high pressure liquid chromatography MS/MS (Q-Exactive) method, to interrogate unbiased proteomic changes in cerebrovessels from AD and healthy control brains on different APOE genotype backgrounds. We first interrogated changes between healthy control homozygote E2/E2, E3/E3 and E4/E4 cases to identify underlying genotype specific effects on cerebrovessels. EIF2 signaling, regulation of eIF4 and 70S6K signaling and mTOR signaling were the top significantly altered pathways in E4/E4 compared to E3/E3 cases. EIF2, nitric oxide and sirtuin signaling pathways were the top significantly altered pathways in E4/E4 compared to E2/E2 cases. We used a Two-way ANOVA analysis to identify AD-dependent changes and their interactions with APOE genotype. The highest number of significantly regulated proteins from this interaction was observed in E3/E4 (192) and E4/E4 (189) cases. As above, EIF2, mTOR signaling and eIF4 and 70S6K signaling were the top three significantly altered pathways in E4 allele carriers (i.e. E3/E4 and E4/E4 genotypes). Of all the cerebrovascular cell specific markers identified in our proteomic analyses, endothelial cell, astrocyte, and smooth muscle cell specific protein markers were significantly altered in E4/E4 cases, while endothelial cells and astrocyte specific protein markers were altered in E3/E4 cases. These proteomic changes provide novel insights to explain the longstanding link between APOE4 and cerebrovascular dysfunction. The early and converging APOE4 dependent changes we identified could provide novel targets in the cerebrovasculature for developing disease modifying strategies to mitigate the effects of APOE4 genotype on increasing the risk for, and the path towards AD pathogenesis.

Dataset Information

SEX-DEPENDENT APOE4 NEUTROPHIL-MICROGLIA INTERACTIONS DRIVE COGNITIVE IMPAIRMENT IN ALZHEIMER'S DISEASE [Microglia_IL17RA]

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