Amyloid-β aggregates activate peripheral monocytes in mild cognitive impairment

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 Romero-Ramos, Christian K. Holm, Gregers R. Andersen, Huaying Zhao, Peter Schuck, Jens V. Nygaard, Duncan S. Sutherland, Simon F. Eskildsen, Thomas E. Willnow, David J. Brooks and Thomas Vorup-Jensen ()
Additional contact information
Kristian Juul-Madsen: Aarhus University, The Skou Building, Høegh-Guldbergs Gade 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
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
Marina Romero-Ramos: 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
Simon F. Eskildsen: Aarhus University, Palle Juul-Jensens Boulevard 11
Thomas E. Willnow: Aarhus University, The Skou Building, Høegh-Guldbergs Gade 10
David J. Brooks: Aarhus University Hospital, Palle Juul-Jensens Boulevard 99
Thomas Vorup-Jensen: Aarhus University, The Skou Building, Høegh-Guldbergs Gade 10

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-45627-y

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