Rosenzweig N, Kleemann KL, Rust T, Carpenter M, Grucci M, Aronchik M, Brouwer N, Valenbreder I, Cooper-Hohn J, Iyer M, Krishnan RK, Sivanathan KN, Brandão W, Yahya T, Durao A, Yin Z, Chadarevian JP, Properzi MJ, Nowarski R, Davtyan H, Weiner HL, Blurton-Jones M, Yang HS, Eggen BJ, Sperling RA, Butovsky O. Sex-dependent APOE4 neutrophil-microglia interactions drive cognitive impairment in Alzheimer's disease. Nat Med. 2024 Oct;30(10):2990-3003. Epub 2024 Jul 3 PubMed.
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Weill College Medicine, New York
This study is of interest as it provides new insights into the sex dependence of the impact of ApoE4 on AD pathobiology. The inclusion of human data combined with experimental validation are major strengths of the paper.
The identification of a new class of IL17-producing neutrophils residing in the meninges and infiltrating the AD brain suggests a link through which meningeal IL17-producing cells can act on microglia in the brain parenchyma through IL17. How neutrophils cross the glia limitans barrier at the brain border to access the brain parenchyma will need to be determined in future studies.
Another interesting aspect is that the study highlights the complexities of using immunomodulation as a therapeutic approach for AD. In females, the presence of ApoE4 in neutrophils confers an immunosuppressive phenotype, which ends up being deleterious by suppressing microglial responses to amyloid pathology. Therefore, immunosuppression to reduce inflammation across the board may not be advisable, as it may promote pathology in female ApoE4 carriers with AD.
The study also highlights the heterogeneity of AD with respect to the impact of sex and ApoE4, and brings attention to the molecular diversity of the pathogenic mechanisms driving neurodegeneration. Gaining further understanding of such mechanistic diversity, related not just to sex and ApoE4 carriage but also to ethnic background, is critically important for individualizing treatments for AD in the community.
The molecular bases for the sexual dimorphism of neutrophil ApoE4 in AD remain to be established, and are worth of further exploration considering the human relevance of the observations provided in this paper.
Washington University in St. Louis, School of Medicine
The study by Rosenzweig et al. on the sex-dependent interactions between APOE4 neutrophils and microglia in Alzheimer's disease is very interesting and important. The authors have elegantly demonstrated the critical role of IL-17 signaling in cognitive impairment, particularly in female APOE4 carriers. They provide compelling evidence for the immunosuppressive phenotype of neutrophils and their impact on microglial function, ultimately affecting cognition. This work contributes to our understanding of the molecular mechanisms underlying Alzheimer's and it opens new avenues for targeted therapeutic interventions.
There is a growing body of research addressing the "neuromodulatory" functions of IL-17 in the brain (Alves de Lima et al., 2020; Ribeiro et al., 2019; Kim et al., 2017; Chen et al., 2017; Choi et al., 2016; Salvador et al., 2021) with most studies focusing on development and homeostasis, highlighting IL-17 signaling directly on neurons. In contrast, Rosenzweig et al. describe more pathological interactions underlying the role of IL-17 in Alzheimer's disease. It would be interesting to see if IL-17 has any effects on other cell types, beyond microglia, in the context of Alzheimer's disease.
References:
Alves de Lima K, Rustenhoven J, Da Mesquita S, Wall M, Salvador AF, Smirnov I, Martelossi Cebinelli G, Mamuladze T, Baker W, Papadopoulos Z, Lopes MB, Cao WS, Xie XS, Herz J, Kipnis J. Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons. Nat Immunol. 2020 Nov;21(11):1421-1429. Epub 2020 Sep 14 PubMed.
Ribeiro M, Brigas HC, Temido-Ferreira M, Pousinha PA, Regen T, Santa C, Coelho JE, Marques-Morgado I, Valente CA, Omenetti S, Stockinger B, Waisman A, Manadas B, Lopes LV, Silva-Santos B, Ribot JC. Meningeal γδ T cell-derived IL-17 controls synaptic plasticity and short-term memory. Sci Immunol. 2019 Oct 11;4(40) PubMed.
Kim S, Kim H, Yim YS, Ha S, Atarashi K, Tan TG, Longman RS, Honda K, Littman DR, Choi GB, Huh JR. Maternal gut bacteria promote neurodevelopmental abnormalities in mouse offspring. Nature. 2017 Sep 28;549(7673):528-532. Epub 2017 Sep 13 PubMed.
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Salvador AF, de Lima KA, Kipnis J. Neuromodulation by the immune system: a focus on cytokines. Nat Rev Immunol. 2021 Mar 1; PubMed.
University of Verona, Italy
Until about 10 years ago, neutrophils were considered a homogenous population of short lived, terminally differentiated cells with low transcriptional capacity that release a limited number of cytokines, suggesting highly conserved, specialized immune and inflammatory functions. However, recent studies, using powerful high-throughput technologies and bioinformatics tools, have revealed unexpected neutrophil phenotypic plasticity and functional diversity. The growing capacity for single-cell analysis in immune cell populations and recent platforms for multicolor flow cytometry and next-generation sequencing have started to provide important insights into the heterogeneity of neutrophils during diseases associated with low grade inflammation, including neurodegenerative disorders.
Neutrophils are now considered key players in neuroinflammatory and neurodegenerative disorders, during which they migrate into the central nervous system (CNS) and meninges, and release harmful molecules that compromise resident brain cell functions. Particularly in animal models of AD, neutrophils infiltrating the CNS release multiple toxic molecules, including myeloperoxidase, elastase, and IL-17, and they contribute to memory loss (Zenaro et al., 2015; Cruz Hernández et al., 2019; Baik et al., 2014). In AD patients, brain-infiltrating neutrophils also release myeloperoxidase, a toxic granule molecule, while circulating neutrophils have an activated phenotype compared to those in control subjects. These changes correlate with faster cognitive decline (Gellhaar et al., 2017; Smyth et al., 2022; Le Page et al., 2017; Dong et al., 2018). In this context, the paper by Rosenzweig et al. provides new exciting data. The authors show that IL-17 producing neutrophils affect microglia phenotypes, promoting neurodegeneration selectively in female APOE4 carriers, suggesting that targeting IL-17F may benefit this population, who are less responsive to current anti-Aβ therapies.
The existence of a neutrophil–microglia interplay has been previously suggested in two animal models of AD (Zenaro et al., 2015), but the molecular mechanisms controlling these cellular interactions and the association with APOE4 in females are key contributions to the understanding of neuroinflammation mechanisms leading to neurodegeneration. Thus, a better knowledge of neutrophil heterogeneity and biology in AD will provide new opportunities for the selective manipulation of this lineage, as recently indicated for cancer therapeutics targeting the migration of suppressive neutrophils and the phenotype reprograming of these cells (Movassagh et al., 2017; Xie et al., 2017; Sahakian et al., 2017; Wang et al., 2017).
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Hong Kong University of Science & Technology
In this study, Rosenzweig and colleagues used comprehensive transcriptomic profiling and multiplex flow cytometry of human blood neutrophils to reveal an immunosuppressive neutrophil subpopulation that expands in female APOE-ε4 carriers who have cognitive impairment. This neutrophil phenotype is characterized by elevated interleukin-17 (IL-17) signaling. The authors used immunohistochemistry analysis and in situ hybridization to detect IL-17+ neutrophils in postmortem brain sections from female patients with Alzheimer’s disease and found that APOE3/4 carriers exhibit greater brain neutrophil density than APOE3/3 carriers.
Deletion of APOE4 in neutrophils in transgenic mouse models of AD reduced immunosuppressive neutrophils, demonstrating the cell-autonomous role of APOE4 in the regulation of neutrophil phenotypes. Furthermore, blockade of the IL-17–IL17RA axis in transgenic mouse models of AD by administration of IL-17–neutralizing antibodies, or deletion of microglial IL-17RA, restored the neurodegenerative microglial gene signature and enhanced Aβ clearance by microglia. These findings collectively demonstrate that, in female APOE4 carriers, neutrophils impair the induction of a beneficial microglial response to brain pathologies, which may contribute to the increased risk of AD in this population.
The study supports the notion that neutrophils contribute to AD pathogenesis. Our recent work investigating the blood transcriptomic profiles of patients with AD also implicates a role of neutrophils in AD (Zhong et al., 2024). Specifically, we performed large-scale RNA sequencing of blood cells from patients with AD and from cognitively normal, age-matched controls from a Hong Kong Chinese cohort. We identified co-expression gene modules that accurately classify AD (up to 93 percent accuracy in an independent validation cohort) and are associated with AD-related endophenotypes (e.g., ATN biomarkers). Furthermore, through single-cell RNA sequencing analysis of the blood, we demonstrated that the most accurate module for AD classification is strongly enriched in neutrophils. Considering these findings with those of Rosenzweig et al. indicates that examining the effects of sex and APOE variant on neutrophil-enriched gene module expression profiles may advance our understanding of the role of neutrophils in AD across different ethnic groups.
Another fascinating aspect is that the authors identified a female APOE4 carrier-specific pathological pathway in AD. We had identified a genetic variant in the IL1RL1 locus that associated with lower AD risk in female APOE-ε4 carriers (Jiang et al., 2022). This variant decreases the expression of the decoy receptor, soluble ST2, to restore the IL-33–ST2L signaling axis in microglia. In turn, this promotes the Aβ-responsive gene signature in microglia and enhances Aβ clearance. The sex- and APOE-dependent differences demonstrated in our previous study and in the present study highlight the importance of considering sex and APOE genotype when investigating AD-associated factors.
In summary, this study advances our understanding of the peripheral–central immune cell crosstalk underlying AD pathogenesis. Importantly, it exemplifies why more effort should focus on the contributions of peripheral cell types to AD to better understand disease mechanisms.
References:
Zhong H, Zhou X, Uhm H, Jiang Y, Cao H, Chen Y, Mak TT, Lo RM, Wong BW, Cheng EY, Mok KY, Chan AL, Kwok TC, Mok VC, Ip FC, Hardy J, Fu AK, Ip NY. Using blood transcriptome analysis for Alzheimer's disease diagnosis and patient stratification. Alzheimers Dement. 2024 Apr;20(4):2469-2484. Epub 2024 Feb 7 PubMed.
Jiang Y, Zhou X, Wong HY, Ouyang L, Ip FC, Chau VM, Lau SF, Wu W, Wong DY, Seo H, Fu WY, Lai NC, Chen Y, Chen Y, Tong EP, Alzheimer’s Disease Neuroimaging Initiative, Mok VC, Kwok TC, Mok KY, Shoai M, Lehallier B, Losada PM, O'Brien E, Porter T, Laws SM, Hardy J, Wyss-Coray T, Masters CL, Fu AK, Ip NY. An IL1RL1 genetic variant lowers soluble ST2 levels and the risk effects of APOE-ε4 in female patients with Alzheimer's disease. Nat Aging. 2022 Jul;2(7):616-634. Epub 2022 Jul 15 PubMed.
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