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DOI | 10.1523/JNEUROSCI.0350-15.2016 |
A beta 40 Reduces P-Glycoprotein at the Blood-Brain Barrier through the Ubiquitin-Proteasome Pathway | |
Hartz, Anika M. S.1,2,3; Zhong, Yu1; Wolf, Andrea3; LeVine, Harry, III1; Miller, David S.4; Bauer, Bjoern3,5 | |
发表日期 | 2016-02-10 |
ISSN | 0270-6474 |
卷号 | 36期号:6页码:1930-1941 |
英文摘要 | Failure to clear amyloid-beta (A beta) from the brain is in part responsible for A beta brain accumulation in Alzheimer's disease (AD). A critical protein for clearing A beta across the blood-brain barrier is the efflux transporter P-glycoprotein (P-gp) in the luminal plasma membrane of the brain capillary endothelium. P-gp is reduced at the blood-brain barrier in AD, which has been shown to be associated with A beta brain accumulation. However, the mechanism responsible for P-gp reduction in AD is not well understood. Here we focused on identifying critical mechanistic steps involved in reducing P-gp in AD. We exposed isolated rat brain capillaries to 100 nM A beta 40, A beta 40, aggregated A beta 40, and A beta 42. We observed that only A beta 40 triggered reduction of P-gp protein expression and transport activity levels; this occurred in a dose-and time-dependent manner. To identify the steps involved in A beta-mediated P-gp reduction, we inhibited protein ubiquitination, protein trafficking, and the ubiquitin-proteasome system, and monitored P-gp protein expression, transport activity, and P-gp-ubiquitin levels. Thus, exposing brain capillaries to A beta 40 triggers ubiquitination, internalization, and proteasomal degradation of P-gp. These findings may provide potential therapeutic targets within the blood-brain barrier to limit P-gp degradation in AD and improve A beta brain clearance. |
英文关键词 | Alzheimer's disease;blood-brain barrier;P-glycoprotein;transporter;ubiquitin-proteasome system |
语种 | 英语 |
WOS记录号 | WOS:000369964500013 |
来源期刊 | JOURNAL OF NEUROSCIENCE |
来源机构 | 美国环保署 |
文献类型 | 期刊论文 |
条目标识符 | http://gcip.llas.ac.cn/handle/2XKMVOVA/60906 |
作者单位 | 1.Univ Kentucky, Sanders Brown Ctr Aging, Lexington, KY 40536 USA; 2.Univ Kentucky, Dept Pharmacol & Nutr Sci, Lexington, KY 40536 USA; 3.Univ Minnesota, Dept Pharm Practice & Pharmaceut Sci, Coll Pharm, Duluth, MN 55812 USA; 4.Natl Inst Environm Hlth Sci, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA; 5.Univ Kentucky, Dept Pharmaceut Sci, Coll Pharm, Lexington, KY 40536 USA |
推荐引用方式 GB/T 7714 | Hartz, Anika M. S.,Zhong, Yu,Wolf, Andrea,et al. A beta 40 Reduces P-Glycoprotein at the Blood-Brain Barrier through the Ubiquitin-Proteasome Pathway[J]. 美国环保署,2016,36(6):1930-1941. |
APA | Hartz, Anika M. S.,Zhong, Yu,Wolf, Andrea,LeVine, Harry, III,Miller, David S.,&Bauer, Bjoern.(2016).A beta 40 Reduces P-Glycoprotein at the Blood-Brain Barrier through the Ubiquitin-Proteasome Pathway.JOURNAL OF NEUROSCIENCE,36(6),1930-1941. |
MLA | Hartz, Anika M. S.,et al."A beta 40 Reduces P-Glycoprotein at the Blood-Brain Barrier through the Ubiquitin-Proteasome Pathway".JOURNAL OF NEUROSCIENCE 36.6(2016):1930-1941. |
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