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Microglial complement receptor 3 regulates brain A beta levels through secreted proteolytic activity

Microglial complement receptor 3 regulates brain A beta levels through secreted proteolytic activity JOURNAL OF EXPERIMENTAL MEDICINE Czirr, E., Castello, N. A., Mosher, K. I., Castellano, J. M., Hinkson, I. V., Lucin, K. M., Baeza-Raja, B., Ryu, J. K., Li, L., Farina, S. N., Belichenko, N. P., Longo, F. M., Akassoglou, K., Britschgi, M., Cirrito, J. R., Wyss-Coray, T. 2017; 214 (4): 1081-1092

Abstract

Recent genetic evidence supports a link between microglia and the complement system in Alzheimer's disease (AD). In this study, we uncovered a novel role for the microglial complement receptor 3 (CR3) in the regulation of soluble ß-amyloid (Aß) clearance independent of phagocytosis. Unexpectedly, ablation of CR3 in human amyloid precursor protein-transgenic mice results in decreased, rather than increased, Aß accumulation. In line with these findings, cultured microglia lacking CR3 are more efficient than wild-type cells at degrading extracellular Aß by secreting enzymatic factors, including tissue plasminogen activator. Furthermore, a small molecule modulator of CR3 reduces soluble Aß levels and Aß half-life in brain interstitial fluid (ISF), as measured by in vivo microdialysis. These results suggest that CR3 limits Aß clearance from the ISF, illustrating a novel role for CR3 and microglia in brain Aß metabolism and defining a potential new therapeutic target in AD.

View details for DOI 10.1084/jem.20162011

View details for Web of Science ID 000398051100015

View details for PubMedID 28298456