Microglial complement receptor 3 regulates brain Aβ levels through secreted proteolytic activity

Eva Czirr, Nicholas A. Castello, Kira I. Mosher, Joseph M. Castellano, Izumi V. Hinkson, Kurt M. Lucin, Bernat Baeza-Raja, Jae Kyu Ryu, Lulin Li, Sasha N. Farina, Nadia P. Belichenko, Frank M. Longo, Katerina Akassoglou, Markus Britschgi, John R. Cirrito, Tony Wyss-Coray

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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 β-amyloid (Aβ) clearance independent of phagocytosis. Unexpectedly, ablation of CR3 in human amyloid precursor protein-transgenic mice results in decreased, rather than increased, Aβ accumulation. In line with these findings, cultured microglia lacking CR3 are more efficient than wild-type cells at degrading extracellular Aβ by secreting enzymatic factors, including tissue plasminogen activator. Furthermore, a small molecule modulator of CR3 reduces soluble Aβ levels and Aβ half-life in brain interstitial fluid (ISF), as measured by in vivo microdialysis. These results suggest that CR3 limits Aβ clearance from the ISF, illustrating a novel role for CR3 and microglia in brain Aβ metabolism and defining a potential new therapeutic target in AD.

Original languageEnglish
Pages (from-to)1081-1092
Number of pages12
JournalJournal of Experimental Medicine
Volume214
Issue number4
DOIs
StatePublished - Apr 1 2017

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    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). Microglial complement receptor 3 regulates brain Aβ levels through secreted proteolytic activity. Journal of Experimental Medicine, 214(4), 1081-1092. https://doi.org/10.1084/jem.20162011