Deane Rashid, Sagare Abhay, Hamm Katie, Parisi Margaret, LaRue Barbra, Guo Huang, Wu Zhenhua, Holtzman David M, Zlokovic Berislav V
Division of Neurovascular Biology, Department of Neurosurgery, Arthur Kornberg Medical Research Building, University of Rochester Medical Center, Rochester, New York 14642, USA.
J Neurosci. 2005 Dec 14;25(50):11495-503. doi: 10.1523/JNEUROSCI.3697-05.2005.
The role of blood-brain barrier (BBB) transport in clearance of amyloid beta-peptide (Abeta) by Abeta immunotherapy is not fully understood. To address this issue, we studied the effects of peripherally and centrally administered Abeta-specific IgG on BBB influx of circulating Abeta and efflux of brain-derived Abeta in APPsw(+/-) mice, a model that develops Alzheimer's disease-like amyloid pathology, and wild-type mice. Our data show that anti-Abeta IgG blocks the BBB influx of circulating Abeta in APPsw(+/-) mice and penetrates into the brain to sequester brain Abeta. In young mice, Abeta-anti-Abeta complexes were cleared from brain to blood by transcytosis across the BBB via the neonatal Fc receptor (FcRn) and the low-density lipoprotein receptor-related protein (LRP), whereas in older mice, there was an age-dependent increase in FcRn-mediated IgG-assisted Abeta BBB efflux and a decrease in LRP-mediated clearance of Abeta-anti-Abeta complexes. Inhibition of the FcRn pathway in older APPsw(+/-) mice blocked clearance of endogenous Abeta40/42 by centrally administered Abeta immunotherapy. Moreover, deletion of the FcRn gene in wild-type mice inhibited clearance of endogenous mouse Abeta40/42 by systemically administered anti-Abeta. Our data suggest that the FcRn pathway at the BBB plays a crucial role in IgG-assisted Abeta removal from the aging brain.
血脑屏障（BBB）转运在β-淀粉样肽（Aβ）免疫治疗清除Aβ中的作用尚未完全明确。为解决这一问题，我们研究了外周和中枢给予Aβ特异性IgG对APPsw(+/-)小鼠（一种出现阿尔茨海默病样淀粉样病理改变的模型）和野生型小鼠循环Aβ的血脑屏障内流及脑源性Aβ外流的影响。我们的数据表明，抗Aβ IgG可阻断APPsw(+/-)小鼠循环Aβ的血脑屏障内流，并穿透进入脑内以隔离脑内Aβ。在幼鼠中，Aβ-抗Aβ复合物通过新生儿Fc受体（FcRn）和低密度脂蛋白受体相关蛋白（LRP）经血脑屏障的转胞吞作用从脑内清除至血液中，而在老年小鼠中，FcRn介导的IgG辅助Aβ血脑屏障外流呈年龄依赖性增加，且LRP介导的Aβ-抗Aβ复合物清除减少。抑制老年APPsw(+/-)小鼠的FcRn途径可阻断中枢给予Aβ免疫治疗对内源性Aβ40/42的清除。此外，野生型小鼠中FcRn基因的缺失可抑制全身给予抗Aβ对内源性小鼠Aβ40/42的清除。我们的数据表明，血脑屏障处的FcRn途径在IgG辅助从衰老脑内清除Aβ中起关键作用。
