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Amyloid-β aggregates activate peripheral monocytes in mild cognitive impairment

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Item Type:Article
Title:Amyloid-β aggregates activate peripheral monocytes in mild cognitive impairment
Creators Name:Juul-Madsen, K. and Parbo, P. and Ismail, R. and Ovesen, P.L. and Schmidt, V. and Madsen, L.S. and Thyrsted, J. and Gierl, S. and Breum, M. and Larsen, A. and Andersen, M.N. and Romero-Ramos, M. and Holm, C.K. and Andersen, G.R. and Zhao, H. and Schuck, P. and Nygaard, J.V. and Sutherland, D.S. and Eskildsen, S.F. and Willnow, T.E. and Brooks, D.J. and Vorup-Jensen, T.
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 (11)C-PiB PET and (18)F-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.
Keywords:Alzheimer Disease, Amyloid beta-Peptides, Cognitive Dysfunction, Integrin alphaXbeta2, Monocytes
Source:Nature Communications
Publisher:Nature Publishing Group
Page Range:1224
Date:9 February 2024
Official Publication:https://doi.org/10.1038/s41467-024-45627-y
PubMed:View item in PubMed

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