TY - JOUR
T1 - Microglial complement receptor 3 regulates brain Aβ levels through secreted proteolytic activity
AU - Czirr, Eva
AU - Castello, Nicholas A.
AU - Mosher, Kira I.
AU - Castellano, Joseph M.
AU - Hinkson, Izumi V.
AU - Lucin, Kurt M.
AU - Baeza-Raja, Bernat
AU - Ryu, Jae Kyu
AU - Li, Lulin
AU - Farina, Sasha N.
AU - Belichenko, Nadia P.
AU - Longo, Frank M.
AU - Akassoglou, Katerina
AU - Britschgi, Markus
AU - Cirrito, John R.
AU - Wyss-Coray, Tony
N1 - Funding Information:
The authors thank Dr. Daniela Berdnik for critical review of the manuscript, Dr. Zhaoqing Ding and Dr. Lusijah Roth for assistance with flow cytometry and FACS, Dr. Hui Zhang for maintaining APP transgenic mice, The Stanford Gene Vector and Virus Core (supported by National Institute of Neurological Disorders and Stroke grant no. P30 NS079375-01A1) for producing the lentiviruses used in this study, and Shaun T. Hund for general support. Funding for this study was provided by the Alexander von Humboldt Foundation (E. Czirr), a Kirschstein National Research Service Award predoctoral fellowship (K.I. Mosher), the Jane Coffin Childs Memorial Fund for Medical Research (J.M. Castellano), the John Douglas French Alzheimer's Foundation (K.M. Lucin), National Institute of Neurological Disorders and Stroke (grant R35 NS097976 to K. Akassoglou), the National Institutes of Health/National Institute on Aging (grant R01 AG042513 to J.R. Cirrito), National Institutes of Health/National Institute of Neurological Disorders and Stroke (grant P01 NS074969 J.R. Cirrito), the Paul F. Glenn Center for the Biology of Aging (T. Wyss-Coray), the Department of Veterans Affairs (T. Wyss-Coray), and the National Institute on Aging (grant AG045034 to T. Wyss-Coray). The authors declare no competing financial interests.
Publisher Copyright:
© 2017 Czirr et al.
PY - 2017/4/1
Y1 - 2017/4/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85020909674&partnerID=8YFLogxK
U2 - 10.1084/jem.20162011
DO - 10.1084/jem.20162011
M3 - Article
C2 - 28298456
AN - SCOPUS:85020909674
SN - 0022-1007
VL - 214
SP - 1081
EP - 1092
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 4
ER -