Amyloid-β aggregates activate peripheral monocytes in mild cognitive impairment
Kristian Juul‐Madsen, Peter Parbo, Rola Ismail, Peter Lund Ovesen, Vanessa Schmidt, Lasse Stensvig Madsen, Jacob Thyrsted, Sarah Gierl, Mihaela Breum, Agnete Larsen, Morten Nørgaard Andersen, Marina Romero‐Ramos, Christian K. Holm, G.R. Andersen, Huaying Zhao, Peter Schuck, Jens Vinge Nygaard, Duncan S. Sutherland, Simon Fristed Eskildsen, Thomas E. Willnow, David J. Brooks, Thomas Vorup‐Jensen
Abstract
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.