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Lookup NU author(s): Emeritus Professor David Brooks
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© The Author(s) 2024. 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.
Author(s): Juul-Madsen K, Parbo P, Ismail R, Ovesen PL, Schmidt V, Madsen LS, Thyrsted J, Gierl S, Breum M, Larsen A, Andersen MN, Romero-Ramos M, Holm CK, Andersen GR, Zhao H, Schuck P, Nygaard JV, Sutherland DS, Eskildsen SF, Willnow TE, Brooks DJ, Vorup-Jensen T
Publication type: Article
Publication status: Published
Journal: Nature Communications
Year: 2024
Volume: 15
Online publication date: 09/02/2024
Acceptance date: 31/01/2024
Date deposited: 27/02/2024
ISSN (electronic): 2041-1723
Publisher: Springer Nature
URL: https://doi.org/10.1038/s41467-024-45627-y
DOI: 10.1038/s41467-024-45627-y
Data Access Statement: All data generated in this study are provided in the Supplementary Information and Source Data files. Video recordings for NTA analysis and original files for flow cytometry are available upon request. Source data are provided with this paper. Codes used for the analysis of the SEM images (in Fig. 1) and hydrodynamic calculations (in Fig. 4) are deposited in the GitHub repository at https://github.com/VingesLDB/2023_NCOMM.
PubMed id: 38336934
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