Amyloid-β aggregates activate peripheral monocytes in mild cognitive impairment

TY - JOUR

T1 - Amyloid-β aggregates activate peripheral monocytes in mild cognitive impairment

AU - Juul-Madsen, Kristian

AU - Parbo, Peter

AU - Ismail, Rola

AU - Ovesen, Peter L

AU - Schmidt, Vanessa

AU - Madsen, Lasse S

AU - Thyrsted, Jacob

AU - Gierl, Sarah

AU - Breum, Mihaela

AU - Larsen, Agnete

AU - Andersen, Morten N

AU - Romero-Ramos, Marina

AU - Holm, Christian K

AU - Andersen, Gregers R

AU - Zhao, Huaying

AU - Schuck, Peter

AU - Nygaard, Jens V

AU - Sutherland, Duncan S

AU - Eskildsen, Simon F

AU - Willnow, Thomas E

AU - Brooks, David J

AU - Vorup-Jensen, Thomas

PY - 2024/2

Y1 - 2024/2

N2 - 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.

AB - 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.

KW - ALZHEIMERS AMYLOID-BETA

KW - Alzheimers sygdom

KW - mild cognetive impairment

KW - Integrin alphaXbeta2

KW - monocytter

KW - Microglial cells

KW - PET

UR - http://www.scopus.com/inward/record.url?scp=85184720923&partnerID=8YFLogxK

U2 - 10.1038/s41467-024-45627-y

DO - 10.1038/s41467-024-45627-y

M3 - Journal article

C2 - 38336934

SN - 2041-1723

VL - 15

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 1224

ER -