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 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.
Chen C, Itakura E, Nelson GM, Sheng M, Laurent P, Fenk LA, Butcher RA, Hegde RS, de Bono M. IL-17 is a neuromodulator of Caenorhabditis elegans sensory responses. Nature. 2017 Feb 2;542(7639):43-48. Epub 2017 Jan 18 PubMed.
Choi GB, Yim YS, Wong H, Kim S, Kim H, Kim SV, Hoeffer CA, Littman DR, Huh JR. The maternal interleukin-17a pathway in mice promotes autism-like phenotypes in offspring. Science. 2016 Feb 26;351(6276):933-9. Epub 2016 Jan 28 PubMed.
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).
References:
Zenaro E, Pietronigro E, Della Bianca V, Piacentino G, Marongiu L, Budui S, Turano E, Rossi B, Angiari S, Dusi S, Montresor A, Carlucci T, Nanì S, Tosadori G, Calciano L, Catalucci D, Berton G, Bonetti B, Constantin G. Neutrophils promote Alzheimer's disease-like pathology and cognitive decline via LFA-1 integrin. Nat Med. 2015 Aug;21(8):880-6. Epub 2015 Jul 27 PubMed.
Cruz Hernández JC, Bracko O, Kersbergen CJ, Muse V, Haft-Javaherian M, Berg M, Park L, Vinarcsik LK, Ivasyk I, Rivera DA, Kang Y, Cortes-Canteli M, Peyrounette M, Doyeux V, Smith A, Zhou J, Otte G, Beverly JD, Davenport E, Davit Y, Lin CP, Strickland S, Iadecola C, Lorthois S, Nishimura N, Schaffer CB. Neutrophil adhesion in brain capillaries reduces cortical blood flow and impairs memory function in Alzheimer's disease mouse models. Nat Neurosci. 2019 Mar;22(3):413-420. Epub 2019 Feb 11 PubMed.
Baik SH, Cha MY, Hyun YM, Cho H, Hamza B, Kim DK, Han SH, Choi H, Kim KH, Moon M, Lee J, Kim M, Irimia D, Mook-Jung I. Migration of neutrophils targeting amyloid plaques in Alzheimer's disease mouse model. Neurobiol Aging. 2014 Jun;35(6):1286-92. Epub 2014 Jan 8 PubMed.
Gellhaar S, Sunnemark D, Eriksson H, Olson L, Galter D. Myeloperoxidase-immunoreactive cells are significantly increased in brain areas affected by neurodegeneration in Parkinson's and Alzheimer's disease. Cell Tissue Res. 2017 May 2; PubMed.
Smyth LC, Murray HC, Hill M, van Leeuwen E, Highet B, Magon NJ, Osanlouy M, Mathiesen SN, Mockett B, Singh-Bains MK, Morris VK, Clarkson AN, Curtis MA, Abraham WC, Hughes SM, Faull RL, Kettle AJ, Dragunow M, Hampton MB. Neutrophil-vascular interactions drive myeloperoxidase accumulation in the brain in Alzheimer's disease. Acta Neuropathol Commun. 2022 Mar 24;10(1):38. PubMed.
Le Page A, Lamoureux J, Bourgade K, Frost EH, Pawelec G, Witkowski JM, Larbi A, Dupuis G, Fülöp T. Polymorphonuclear Neutrophil Functions are Differentially Altered in Amnestic Mild Cognitive Impairment and Mild Alzheimer's Disease Patients. J Alzheimers Dis. 2017;60(1):23-42. PubMed.
Dong Y, Lagarde J, Xicota L, Corne H, Chantran Y, Chaigneau T, Crestani B, Bottlaender M, Potier MC, Aucouturier P, Dorothée G, Sarazin M, Elbim C. Neutrophil hyperactivation correlates with Alzheimer's disease progression. Ann Neurol. 2018 Feb;83(2):387-405. PubMed.
Movassagh H, Saati A, Nandagopal S, Mohammed A, Tatari N, Shan L, Duke-Cohan JS, Fowke KR, Lin F, Gounni AS. Chemorepellent Semaphorin 3E Negatively Regulates Neutrophil Migration In Vitro and In Vivo. J Immunol. 2017 Feb 1;198(3):1023-1033. Epub 2016 Dec 2 PubMed.
Xie D, Liu Z, Wu J, Feng W, Yang K, Deng J, Tian G, Santos S, Cui X, Lin F. The effects of activin A on the migration of human breast cancer cells and neutrophils and their migratory interaction. Exp Cell Res. 2017 Aug 1;357(1):107-115. Epub 2017 May 4 PubMed.
Sahakian E, Chen J, Powers JJ, Chen X, Maharaj K, Deng SL, Achille AN, Lienlaf M, Wang HW, Cheng F, Sodré AL, Distler A, Xing L, Perez-Villarroel P, Wei S, Villagra A, Seto E, Sotomayor EM, Horna P, Pinilla-Ibarz J. Essential role for histone deacetylase 11 (HDAC11) in neutrophil biology. J Leukoc Biol. 2017 Aug;102(2):475-486. Epub 2017 May 26 PubMed.
Wang HF, Ning F, Liu ZC, Wu L, Li ZQ, Qi YF, Zhang G, Wang HS, Cai SH, Du J. Histone deacetylase inhibitors deplete myeloid-derived suppressor cells induced by 4T1 mammary tumors in vivo and in vitro. Cancer Immunol Immunother. 2017 Mar;66(3):355-366. Epub 2016 Dec 3 PubMed.
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