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. WillnowDavid J. Brooks, Thomas Vorup-Jensen*

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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.

OriginalsprogEngelsk
Artikelnummer1224
TidsskriftNature Communications
Vol/bind15
Antal sider20
ISSN2041-1723
DOI
StatusUdgivet - 9. feb. 2024

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© The Author(s) 2024.

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