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Amyloid-β aggregates activate peripheral monocytes in mild cognitive impairment

Author

Listed:
  • Kristian Juul-Madsen

    (Aarhus University, The Skou Building, Høegh-Guldbergs Gade 10
    Max-Delbrueck-Center for Molecular Medicine, Robert-Rössle-Str. 10)

  • Peter Parbo

    (Odense University Hospital)

  • Rola Ismail

    (Vejle Hospital, Beriderbakken 4)

  • Peter L. Ovesen

    (Max-Delbrueck-Center for Molecular Medicine, Robert-Rössle-Str. 10)

  • Vanessa Schmidt

    (Max-Delbrueck-Center for Molecular Medicine, Robert-Rössle-Str. 10)

  • Lasse S. Madsen

    (Aarhus University Hospital, Palle Juul-Jensens Boulevard 99
    Aarhus University, Palle Juul-Jensens Boulevard 11
    Aarhus University and Aarhus University Hospital, Building 1710, Universitetsbyen 3)

  • Jacob Thyrsted

    (Aarhus University, The Skou Building, Høegh-Guldbergs Gade 10)

  • Sarah Gierl

    (Aarhus University, The Skou Building, Høegh-Guldbergs Gade 10)

  • Mihaela Breum

    (Aarhus University, The Skou Building, Høegh-Guldbergs Gade 10)

  • Agnete Larsen

    (Aarhus University, The Skou Building, Høegh-Guldbergs Gade 10)

  • Morten N. Andersen

    (Aarhus University, The Skou Building, Høegh-Guldbergs Gade 10
    Aarhus University, Palle Juul-Jensens Boulevard 11
    Aarhus University Hospital, Palle Juul-Jensens Boulevard 99)

  • Marina Romero-Ramos

    (Aarhus University, The Skou Building, Høegh-Guldbergs Gade 10
    Aarhus University, The Skou Building, Høegh-Guldbergs Gade 10)

  • Christian K. Holm

    (Aarhus University, The Skou Building, Høegh-Guldbergs Gade 10)

  • Gregers R. Andersen

    (Aarhus University, Universitetsbyen 81)

  • Huaying Zhao

    (National Institute of Biomedical Imaging and Bioengineering, Building 31, 9000 Rockville Pike)

  • Peter Schuck

    (National Institute of Biomedical Imaging and Bioengineering, Building 31, 9000 Rockville Pike)

  • Jens V. Nygaard

    (Aarhus University, Gustav Wieds vej 10 D)

  • Duncan S. Sutherland

    (Interdisiciplinary Nanoscience Center, Aarhus University, The iNANO House, Gustav Wieds Vej 14
    Center for Cellular Signal Patterns, Aarhus University, The iNANO House, Gustav Wieds Vej 14)

  • Simon F. Eskildsen

    (Aarhus University, Palle Juul-Jensens Boulevard 11
    Aarhus University and Aarhus University Hospital, Building 1710, Universitetsbyen 3)

  • Thomas E. Willnow

    (Aarhus University, The Skou Building, Høegh-Guldbergs Gade 10
    Max-Delbrueck-Center for Molecular Medicine, Robert-Rössle-Str. 10)

  • David J. Brooks

    (Aarhus University Hospital, Palle Juul-Jensens Boulevard 99
    Imperial College London, Burlington Danes, The Hammersmith Hospital, Du Cane Road
    University of Newcastle, Framlington Place)

  • Thomas Vorup-Jensen

    (Aarhus University, The Skou Building, Høegh-Guldbergs Gade 10
    Aarhus University, The Skou Building, Høegh-Guldbergs Gade 10
    Interdisiciplinary Nanoscience Center, Aarhus University, The iNANO House, Gustav Wieds Vej 14)

Abstract

The peripheral immune system is important in neurodegenerative diseases, both in protecting and inflaming the brain, but the underlying mechanisms remain elusive. Alzheimer’s Disease is commonly preceded by a prodromal period. Here, we report the presence of large Aβ aggregates in plasma from patients with mild cognitive impairment (n = 38). The aggregates are associated with low level Alzheimer’s Disease-like brain pathology as observed by 11C-PiB PET and 18F-FTP PET and lowered CD18-rich monocytes. We characterize complement receptor 4 as a strong binder of amyloids and show Aβ aggregates are preferentially phagocytosed and stimulate lysosomal activity through this receptor in stem cell-derived microglia. KIM127 integrin activation in monocytes promotes size selective phagocytosis of Aβ. Hydrodynamic calculations suggest Aβ aggregates associate with vessel walls of the cortical capillaries. In turn, we hypothesize aggregates may provide an adhesion substrate for recruiting CD18-rich monocytes into the cortex. Our results support a role for complement receptor 4 in regulating amyloid homeostasis.

Suggested Citation

  • Kristian Juul-Madsen & Peter Parbo & Rola Ismail & Peter L. Ovesen & Vanessa Schmidt & Lasse S. Madsen & Jacob Thyrsted & Sarah Gierl & Mihaela Breum & Agnete Larsen & Morten N. Andersen & Marina Rome, 2024. "Amyloid-β aggregates activate peripheral monocytes in mild cognitive impairment," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45627-y
    DOI: 10.1038/s41467-024-45627-y
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    References listed on IDEAS

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    1. C. Hansen & D. Bay & M.R. Jensen & B. Gervang & H.M. Jensen & S.A. Thrysøe & J.V. Nygaard, 2014. "Numerical simulation of LDL transport through the carotid arterial wall," Computer Methods in Biomechanics and Biomedical Engineering, Taylor & Francis Journals, vol. 17(S1), pages 20-21, August.
    2. Krzysztof Kucharz & Kasper Kristensen & Kasper Bendix Johnsen & Mette Aagaard Lund & Micael Lønstrup & Torben Moos & Thomas Lars Andresen & Martin Johannes Lauritzen, 2021. "Post-capillary venules are the key locus for transcytosis-mediated brain delivery of therapeutic nanoparticles," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    3. Hossein Mohammad-Beigi & Yuya Hayashi & Christina Moeslund Zeuthen & Hoda Eskandari & Carsten Scavenius & Kristian Juul-Madsen & Thomas Vorup-Jensen & Jan J. Enghild & Duncan S. Sutherland, 2020. "Mapping and identification of soft corona proteins at nanoparticles and their impact on cellular association," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
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