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

被引：98

作者：

Czirr, Eva ^{[1
,9
]}

Castello, Nicholas A. ^{[4
]}

Mosher, Kira I. ^{[1
]}

Castellano, Joseph M. ^{[1
,2
]}

Hinkson, Izumi V. ^{[1
,2
,3
]}

Lucin, Kurt M. ^{[1
,10
]}

Baeza-Raja, Bernat ^{[4
]}

Ryu, Jae Kyu ^{[4
]}

Li, Lulin ^{[1
,2
,3
]}

Farina, Sasha N. ^{[1
,3
]}

Belichenko, Nadia P. ^{[1
]}

Longo, Frank M. ^{[1
]}

Akassoglou, Katerina ^{[4
,5
]}

Britschgi, Markus ^{[1
,11
]}

Cirrito, John R. ^{[6
,7
,8
]}

Wyss-Coray, Tony ^{[1
,2
,3
]}

机构：

[1] Stanford Univ, Sch Med, Dept Neurol & Neurol Sci, Stanford, CA 94305 USA

[2] Stanford Univ, Sch Med, Paul F Glenn Ctr Biol Aging, Stanford, CA 94305 USA

[3] Vet Affairs Palo Alto Hlth Care Syst, Ctr Tissue Regenerat Repair & Restorat, Palo Alto, CA 94304 USA

[4] Univ Calif San Francisco, Gladstone Inst Neurol Dis, San Francisco, CA 94158 USA

[5] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94158 USA

[6] Washington Univ, Dept Neurol, St Louis, MO 63110 USA

[7] Washington Univ, Med Ctr, Knight Alzheimers Dis Res Ctr, St Louis, MO 63110 USA

[8] Washington Univ, Hope Ctr Neurol Disorders, St Louis, MO 63110 USA

[9] Alkahest Inc, San Carlos, CA 94070 USA

[10] Eastern Connecticut State Univ, Willimantic, CT 06226 USA

[11] Roche Innovat Ctr Basel, Neurosci Discovery, Roche Pharmaceut Res & Early Dev, CH-4070 Basel, Switzerland

来源：

JOURNAL OF EXPERIMENTAL MEDICINE | 2017年 / 214卷 / 04期

基金：

美国国家卫生研究院;

关键词：

TISSUE-PLASMINOGEN ACTIVATOR; ALZHEIMERS-DISEASE BRAIN; GAMMA-SECRETASE; INTEGRIN CD11B/CD18; AMYLOID PLAQUES; TRANSGENIC MICE; NERVOUS-SYSTEM; APP/PS1; MICE; MOUSE MODELS; IN-VIVO;

D O I：

10.1084/jem.20162011

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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

引用

页码：1081 / 1092

页数：12

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