Amyloid-beta aggregates activate peripheral monocytes in mild cognitive impairment.
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 Abeta 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 Abeta 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 Abeta. Hydrodynamic calculations suggest Abeta 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.
| Authors: | 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, |
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| Journal: | Nat Commun;2024Feb09; 15 (1) 1224. doi:10.1038/s41467-024-45627-y |
| Year: | 2024 |
| PubMed: | PMID: 38336934 (Go to PubMed) |