Brain Insulin Impairs Amyloid-β(1-40) Clearance from the Brain
Brain Insulin Impairs Amyloid-β(1-40) Clearance from the Brain
复制标题
脑胰岛素会损害大脑中淀粉样蛋白-β(1-40) 的清除
DOI：
10.1523/jneurosci.2236-04.2004
复制
发表时间：
2004
期刊：
影响因子：
--
通讯作者：
T. Terasaki
中科院分区：
文献类型：
--
作者：
T. Shiiki;S. Ohtsuki;A. Kurihara;H. Naganuma;K. Nishimura;M. Tachikawa;K. Hosoya;T. Terasaki
脑淀粉样蛋白-β肽(A-β)清除在决定脑内A-β水平中起着关键作用，但其机制尚不清楚。在这项研究中，我们使用脑外流指数法研究了脑A-β跨血脑屏障的清除。[125I]β(1-40)从大鼠脑内清除到循环血中，半衰期为48.8min，半饱和浓度为8.15 nm。23月龄大鼠的A-β(1-40)清除率比7周龄降低30.5%。脑内给药后血浆中检测到完整的A-β(1-40)形式，提示A-β(1-40)发生了外流转运。联合应用100βg/ml胰岛素和1 mM硫吗芬，Aμ(1-40)清除率分别降低44.6%和34.0%。联合应用胰岛素可增加脑内完整的[125I]Aβ(1-40)水平。在胰岛素降解酶抑制剂中，杆菌肽抑制消除速率，而N-乙基马来酰亚胺和金属螯合剂不起作用。受体相关蛋白、岩藻糖胶、3-bromo-5-t-butyl-4-hydroxy-benzylidenemalonitrile，抗胰岛素样生长因子-I受体抗体和L酪氨酸不影响Aβ(1-40)的清除率，提示相关受体或转运体可能不参与这一清除过程。综上所述，本研究证实了蛋白质降解过程和胰岛素敏感过程参与了大鼠脑内Aβ(1-40)的清除。
Cerebral amyloid-β peptide (Aβ) clearance plays a key role in determining the brain level of Aβ; however, its mechanism remains unclear. In this study, we investigated cerebral Aβ clearance across the blood-brain barrier (BBB) by using the Brain Efflux Index method. [125I]Aβ(1-40) was eliminated from rat brain to circulating blood with a half-life of 48.8 min and a half-saturation concentration of 8.15 nm. The Aβ(1-40) elimination rate was reduced by 30.5% in 23-month-old rats compared with 7-week-old rats. The intact form of Aβ(1-40) was detected in plasma after intracerebral administration, indicating the occurrence of efflux transport of intact Aβ(1-40). The Aβ(1-40) elimination rate was significantly inhibited by coadministration of 100 μg/ml insulin and 1 mm thiorphan by 44.6 and 34.0%, respectively. The level of intact [125I]Aβ(1-40) in the brain was increased by coadministration of insulin. Among insulin-degrading enzyme inhibitors, bacitracin inhibited the elimination rate, whereas N-ethylmaleimide and metal chelators had no effect. Receptor-associated protein, fucoidan, 3-bromo-5-t-butyl-4-hydroxy-benzylidenemalonitrile, anti-IGF-I receptor antibody, and l-tyrosine did not affect the Aβ(1-40) elimination rate, suggesting that the relevant receptors or transporters are not likely to be involved in the clearance. In conclusion, the present study has demonstrated the involvement of a proteolytic degradation process and an insulin-sensitive process in cerebral Aβ(1-40) clearance in the rat.
影响因子：
15.9
作者：
Shibata, M;Yamada, S;Zlokovic, BV
通讯作者：
Zlokovic, BV
影响因子：
9.8
作者：
DUFFY, KR;PARDRIDGE, WM;ROSENFELD, RG
通讯作者：
ROSENFELD, RG