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Amyloid-β aggregates activate peripheral monocytes in mild cognitive impairment

Lookup NU author(s): Emeritus Professor David Brooks

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 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.


Publication metadata

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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Funding

Funder referenceFunder name
3101-00104B
820636
Aarhus University Research Foundation
Aarhus University Research Foundation AU IDEAS 2013 grant NEURODIN
2030-00002B
4004-00305
CellPAT - DNRF135
AUFF-E-2015-FLS-9-6
Danish Alzheimer Association
Danish National Research Foundation
European Union Horizon 2020
Independent Research Fund Denmark
Intramural Research Program, NIH NIBIB
Lundbeckfonden
NNF19OC0058516
Novo Nordisk Foundation
NNF21OC0071574
R380-2021-1326

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