IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-56833-7.html
   My bibliography  Save this article

A single-cell atlas to map sex-specific gene-expression changes in blood upon neurodegeneration

Author

Listed:
  • Friederike Grandke

    (Saarland University)

  • Tobias Fehlmann

    (Saarland University)

  • Fabian Kern

    (Saarland University
    Saarland University Campus)

  • David M. Gate

    (Stanford University
    Veterans Administration Palo Alto Healthcare System
    Stanford University
    Stanford University)

  • Tobias William Wolff

    (Saarland University)

  • Olivia Leventhal

    (Stanford University)

  • Divya Channappa

    (Stanford University)

  • Pascal Hirsch

    (Saarland University)

  • Edward N. Wilson

    (Stanford University)

  • Eckart Meese

    (Saarland University)

  • Chuanyu Liu

    (MGI Group)

  • Quan Shi

    (MGI Group)

  • Matthias Flotho

    (Saarland University)

  • Yongping Li

    (Saarland University
    MGI Group)

  • Cynthia Chen

    (MGI Group)

  • Yeya Yu

    (MGI Group)

  • Jiangshan Xu

    (MGI Group)

  • Michael Junkin

    (MGI Group)

  • Zhifeng Wang

    (MGI Group)

  • Tao Wu

    (MGI Group)

  • Longqi Liu

    (MGI Group)

  • Yong Hou

    (MGI Group)

  • Katrin I. Andreasson

    (Stanford University
    Stanford University
    Stanford University)

  • Jenny S. Gansen

    (Saarland University)

  • Elvira Mass

    (University of Bonn)

  • Kathleen Poston

    (Stanford University)

  • Tony Wyss-Coray

    (Stanford University
    Veterans Administration Palo Alto Healthcare System
    Stanford University
    Stanford University)

  • Andreas Keller

    (Saarland University
    Saarland University Campus
    Stanford University
    Saarland University Campus)

Abstract

The clinical course and treatment of neurodegenerative disease are complicated by immune-system interference and chronic inflammatory processes, which remain incompletely understood. Mapping immune signatures in larger human cohorts through single-cell gene expression profiling supports our understanding of observed peripheral changes in neurodegeneration. Here, we employ single-cell gene expression profiling of over 909k peripheral blood mononuclear cells (PBMCs) from 121 healthy individuals, 48 patients with mild cognitive impairment (MCI), 46 with Parkinson’s disease (PD), 27 with Alzheimer’s disease (AD), and 15 with both PD and MCI. The dataset is interactively accessible through a freely available website ( https://www.ccb.uni-saarland.de/adrcsc ). In this work, we identify disease-associated changes in blood cell type composition and the gene expression in a sex-specific manner, offering insights into peripheral and solid tissue signatures in AD and PD.

Suggested Citation

  • Friederike Grandke & Tobias Fehlmann & Fabian Kern & David M. Gate & Tobias William Wolff & Olivia Leventhal & Divya Channappa & Pascal Hirsch & Edward N. Wilson & Eckart Meese & Chuanyu Liu & Quan Sh, 2025. "A single-cell atlas to map sex-specific gene-expression changes in blood upon neurodegeneration," Nature Communications, Nature, vol. 16(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56833-7
    DOI: 10.1038/s41467-025-56833-7
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-56833-7
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-025-56833-7?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. David Gate & Naresha Saligrama & Olivia Leventhal & Andrew C. Yang & Michael S. Unger & Jinte Middeldorp & Kelly Chen & Benoit Lehallier & Divya Channappa & Mark B. Los Santos & Alisha McBride & John , 2020. "Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer’s disease," Nature, Nature, vol. 577(7790), pages 399-404, January.
    2. Hansruedi Mathys & Jose Davila-Velderrain & Zhuyu Peng & Fan Gao & Shahin Mohammadi & Jennie Z. Young & Madhvi Menon & Liang He & Fatema Abdurrob & Xueqiao Jiang & Anthony J. Martorell & Richard M. Ra, 2019. "Author Correction: Single-cell transcriptomic analysis of Alzheimer’s disease," Nature, Nature, vol. 571(7763), pages 1-1, July.
    3. Francisco J. Garcia & Na Sun & Hyeseung Lee & Brianna Godlewski & Hansruedi Mathys & Kyriaki Galani & Blake Zhou & Xueqiao Jiang & Ayesha P. Ng & Julio Mantero & Li-Huei Tsai & David A. Bennett & Must, 2022. "Single-cell dissection of the human brain vasculature," Nature, Nature, vol. 603(7903), pages 893-899, March.
    4. Andrew C. Yang & Ryan T. Vest & Fabian Kern & Davis P. Lee & Maayan Agam & Christina A. Maat & Patricia M. Losada & Michelle B. Chen & Nicholas Schaum & Nathalie Khoury & Angus Toland & Kruti Calcutta, 2022. "A human brain vascular atlas reveals diverse mediators of Alzheimer’s risk," Nature, Nature, vol. 603(7903), pages 885-892, March.
    5. Hansruedi Mathys & Jose Davila-Velderrain & Zhuyu Peng & Fan Gao & Shahin Mohammadi & Jennie Z. Young & Madhvi Menon & Liang He & Fatema Abdurrob & Xueqiao Jiang & Anthony J. Martorell & Richard M. Ra, 2019. "Single-cell transcriptomic analysis of Alzheimer’s disease," Nature, Nature, vol. 570(7761), pages 332-337, June.
    6. Andrew C. Yang & Marc Y. Stevens & Michelle B. Chen & Davis P. Lee & Daniel Stähli & David Gate & Kévin Contrepois & Winnie Chen & Tal Iram & Lichao Zhang & Ryan T. Vest & Aisling Chaney & Benoit Leha, 2020. "Physiological blood–brain transport is impaired with age by a shift in transcytosis," Nature, Nature, vol. 583(7816), pages 425-430, July.
    7. Joel W. Blanchard & Leyla Anne Akay & Jose Davila-Velderrain & Djuna Maydell & Hansruedi Mathys & Shawn M. Davidson & Audrey Effenberger & Chih-Yu Chen & Kristal Maner-Smith & Ihab Hajjar & Eric A. Or, 2022. "APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes," Nature, Nature, vol. 611(7937), pages 769-779, November.
    8. M. Büttner & J. Ostner & C. L. Müller & F. J. Theis & B. Schubert, 2021. "scCODA is a Bayesian model for compositional single-cell data analysis," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
    9. Andrew C. Yang & Fabian Kern & Patricia M. Losada & Maayan R. Agam & Christina A. Maat & Georges P. Schmartz & Tobias Fehlmann & Julian A. Stein & Nicholas Schaum & Davis P. Lee & Kruti Calcuttawala &, 2021. "Dysregulation of brain and choroid plexus cell types in severe COVID-19," Nature, Nature, vol. 595(7868), pages 565-571, July.
    10. Andrew C. Yang & Fabian Kern & Patricia M. Losada & Maayan R. Agam & Christina A. Maat & Georges P. Schmartz & Tobias Fehlmann & Julian A. Stein & Nicholas Schaum & Davis P. Lee & Kruti Calcuttawala &, 2021. "Publisher Correction: Dysregulation of brain and choroid plexus cell types in severe COVID-19," Nature, Nature, vol. 598(7882), pages 4-4, October.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Özkan İş & Xue Wang & Joseph S. Reddy & Yuhao Min & Elanur Yilmaz & Prabesh Bhattarai & Tulsi Patel & Jeremiah Bergman & Zachary Quicksall & Michael G. Heckman & Frederick Q. Tutor-New & Birsen Can De, 2024. "Gliovascular transcriptional perturbations in Alzheimer’s disease reveal molecular mechanisms of blood brain barrier dysfunction," Nature Communications, Nature, vol. 15(1), pages 1-23, December.
    2. Ricardo Martins-Ferreira & Josep Calafell-Segura & Bárbara Leal & Javier Rodríguez-Ubreva & Elena Martínez-Saez & Elisabetta Mereu & Paulo Pinho E Costa & Ariadna Laguna & Esteban Ballestar, 2025. "The Human Microglia Atlas (HuMicA) unravels changes in disease-associated microglia subsets across neurodegenerative conditions," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    3. Nicola A. Kearns & Artemis Iatrou & Daniel J. Flood & Sashini Tissera & Zachary M. Mullaney & Jishu Xu & Chris Gaiteri & David A. Bennett & Yanling Wang, 2023. "Dissecting the human leptomeninges at single-cell resolution," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    4. Cankun Wang & Diana Acosta & Megan McNutt & Jiang Bian & Anjun Ma & Hongjun Fu & Qin Ma, 2024. "A single-cell and spatial RNA-seq database for Alzheimer’s disease (ssREAD)," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    5. Hyun-Sik Yang & Ling Teng & Daniel Kang & Vilas Menon & Tian Ge & Hilary K. Finucane & Aaron P. Schultz & Michael Properzi & Hans-Ulrich Klein & Lori B. Chibnik & Julie A. Schneider & David A. Bennett, 2023. "Cell-type-specific Alzheimer’s disease polygenic risk scores are associated with distinct disease processes in Alzheimer’s disease," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    6. Qi Wang & Jerry Antone & Eric Alsop & Rebecca Reiman & Cory Funk & Jaroslav Bendl & Joel T. Dudley & Winnie S. Liang & Timothy L. Karr & Panos Roussos & David A. Bennett & Philip L. Jager & Geidy E. S, 2024. "Single cell transcriptomes and multiscale networks from persons with and without Alzheimer’s disease," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    7. Matthew J. Leventhal & Camila A. Zanella & Byunguk Kang & Jiajie Peng & David Gritsch & Zhixiang Liao & Hassan Bukhari & Tao Wang & Ping-Chieh Pao & Serwah Danquah & Joseph Benetatos & Ralda Nehme & S, 2025. "An integrative systems-biology approach defines mechanisms of Alzheimer’s disease neurodegeneration," Nature Communications, Nature, vol. 16(1), pages 1-21, December.
    8. Mirren Charnley & Saba Islam & Guneet K. Bindra & Jeremy Engwirda & Julian Ratcliffe & Jiangtao Zhou & Raffaele Mezzenga & Mark D. Hulett & Kyunghoon Han & Joshua T. Berryman & Nicholas P. Reynolds, 2022. "Neurotoxic amyloidogenic peptides in the proteome of SARS-COV2: potential implications for neurological symptoms in COVID-19," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    9. Nelson Johansen & Hongru Hu & Gerald Quon, 2023. "Projecting RNA measurements onto single cell atlases to extract cell type-specific expression profiles using scProjection," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    10. Hannah Drew Rickner & Lulu Jiang & Rui Hong & Nicholas K. O’Neill & Chromewell A. Mojica & Benjamin J. Snyder & Lushuang Zhang & Dipan Shaw & Maria Medalla & Benjamin Wolozin & Christine S. Cheng, 2022. "Single cell transcriptomic profiling of a neuron-astrocyte assembloid tauopathy model," Nature Communications, Nature, vol. 13(1), pages 1-22, December.
    11. Jingtao Wang & Gregory J. Fonseca & Jun Ding, 2024. "scSemiProfiler: Advancing large-scale single-cell studies through semi-profiling with deep generative models and active learning," Nature Communications, Nature, vol. 15(1), pages 1-27, December.
    12. Yunhe Wang & Binbin Su & Junqing Xie & Clemente Garcia-Rizo & Daniel Prieto-Alhambra, 2024. "Long-term risk of psychiatric disorder and psychotropic prescription after SARS-CoV-2 infection among UK general population," Nature Human Behaviour, Nature, vol. 8(6), pages 1076-1087, June.
    13. Haven Tillmon & Breeanne M. Soteros & Liang Shen & Qifei Cong & Mackenna Wollet & Julianne General & Hanna Chin & John Beichen Lee & Flavia R. Carreno & David A. Morilak & Jun Hee Kim & Gek Ming Sia, 2024. "Complement and microglia activation mediate stress-induced synapse loss in layer 2/3 of the medial prefrontal cortex in male mice," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    14. Zoeb Jiwaji & Sachin S. Tiwari & Rolando X. Avilés-Reyes & Monique Hooley & David Hampton & Megan Torvell & Delinda A. Johnson & Jamie McQueen & Paul Baxter & Kayalvizhi Sabari-Sankar & Jing Qiu & Xin, 2022. "Reactive astrocytes acquire neuroprotective as well as deleterious signatures in response to Tau and Aß pathology," Nature Communications, Nature, vol. 13(1), pages 1-23, December.
    15. Zu-Qiang Liu & Hao Dai & Lu Yao & Wei-Feng Chen & Yun Wang & Li-Yun Ma & Xiao-Qing Li & Sheng-Li Lin & Meng-Jiang He & Ping-Ting Gao & Xin-Yang Liu & Jia-Xin Xu & Xiao-Yue Xu & Ke-Hao Wang & Li Wang &, 2023. "A single-cell transcriptional landscape of immune cells shows disease-specific changes of T cell and macrophage populations in human achalasia," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    16. Chang Su & Zichun Xu & Xinning Shan & Biao Cai & Hongyu Zhao & Jingfei Zhang, 2023. "Cell-type-specific co-expression inference from single cell RNA-sequencing data," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    17. Jia-Ru Wei & Zhao-Zhe Hao & Chuan Xu & Mengyao Huang & Lei Tang & Nana Xu & Ruifeng Liu & Yuhui Shen & Sarah A. Teichmann & Zhichao Miao & Sheng Liu, 2022. "Identification of visual cortex cell types and species differences using single-cell RNA sequencing," Nature Communications, Nature, vol. 13(1), pages 1-21, December.
    18. BaDoi N. Phan & Madelyn H. Ray & Xiangning Xue & Chen Fu & Robert J. Fenster & Stephen J. Kohut & Jack Bergman & Suzanne N. Haber & Kenneth M. McCullough & Madeline K. Fish & Jill R. Glausier & Qiao S, 2024. "Single nuclei transcriptomics in human and non-human primate striatum in opioid use disorder," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    19. Harris E. Blankenship & Kelsey A. Carter & Kevin D. Pham & Nina T. Cassidy & Andrea N. Markiewicz & Michael I. Thellmann & Amanda L. Sharpe & Willard M. Freeman & Michael J. Beckstead, 2024. "VTA dopamine neurons are hyperexcitable in 3xTg-AD mice due to casein kinase 2-dependent SK channel dysfunction," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    20. Osama Al-Dalahmah & Michael G. Argenziano & Adithya Kannan & Aayushi Mahajan & Julia Furnari & Fahad Paryani & Deborah Boyett & Akshay Save & Nelson Humala & Fatima Khan & Juncheng Li & Hong Lu & Yu S, 2023. "Re-convolving the compositional landscape of primary and recurrent glioblastoma reveals prognostic and targetable tissue states," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56833-7. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.