Modulation of Na+ ,K+ pumping and neurotransmitter uptake by beta-amyloid

	Modulation of Na+ ,K+ pumping and neurotransmitter uptake by beta-amyloid
	Gu, QB; Zhao, JX; Fei, J; Schwarz, W
刊名	NEUROSCIENCE
	2004
卷号	126 期号:1 页码:61-67
关键词	Na+ glutamate transporter GABA transporter Alzheimer's disease Xenopus oocyte K+-ATPase
通讯作者	Schwarz, W (reprint author), Max Planck Inst Biophys, Marie Curie Str 15, Frankfurt, Germany.,schwarz@mpibp-frankfurt.mpg.de
英文摘要	Micromolar concentrations of beta-amyloid (Abeta), a 40/42-amino-acid-long proteolytic fragment (Abeta(1-40/42)) of the amyloid precursor protein, was shown previously to play a crucial role in pathogenesis of Alzheimer's disease. We used the Xenopus oocyte expression system to investigate specific effects of micromolar concentrations of Abeta(1-42) on the neurotransmitter transporters for gamma-aminobutyric acid (GABA), GAT1, and for the excitatory amino acid glutamate, EAAC1, which are driven by the transmembrane Na+ gradient that is regulated by the Na+,K+-ATPase. Brief treatment with Abeta(1-42), up to 80 min, leads to a significant inhibition of ion translocation by the Na+, K+-ATPase (30-40%); also glutamate uptake is inhibited (20%) while GABA uptake is not affected. Since reduced glutamate uptake will result in elevated, neurotoxic concentrations of extracellular glutamate, we investigated the effects of Abeta(1-42) and the smaller fragments, Abeta(12-28) and Abeta(25-35), on EAAC1 in more detail. Prolonged incubation in 1 muM Abeta(1-42) leads to further, strong inhibition of glutamate uptake and EAAC1-mediated current (after 4 h inhibition amounts to more than 80%). Abeta(12-28) is less effective with 50% inhibition after 4 h of incubation at 20 muM. Abeta(1-42) and Abeta(12-28) affect EAAC1-mediated current to a similar extent as the rate of glutamate uptake. The effects on EAAC1-mediated current are irreversible if Abeta were applied for longer time periods. Peptides directly microinjected into the oocyte are ineffective suggesting that the observed effect were mediated by extracellular proteins. Abeta(25-35) hardly affects EAAC1-mediated current or glutamate uptake. The results demonstrate that Abeta specifically inhibits the Na+,K+ pump and EAAC1. The domain between amino acids 12 and 28 of Abeta seems to play a crucial role for inhibition of EAAC1. The inhibition of EAAC1 by neurotoxic, elevated extracellular glutamate levels may contribute to Alzheimer's pathogenesis. (C) 2004 IBRO. Published by Elsevier Ltd. All rights reserved.
学科主题	Neurosciences & Neurology
类目[WOS]	Neurosciences
关键词[WOS]	NICOTINIC ACETYLCHOLINE-RECEPTORS ; ALZHEIMERS-DISEASE ; SODIUM-PUMP ; HIPPOCAMPAL-NEURONS ; XENOPUS OOCYTES ; EXTERNAL K+ ; PEPTIDE ; PROTEIN ; ATPASE ; PHOSPHORYLATION
收录类别	SCI
语种	英语
WOS记录号	WOS:000221707100006
内容类型	期刊论文
版本	出版稿
源URL	[http://202.127.25.143/handle/331003/2029]
专题	上海生化细胞研究所_上海生科院生化细胞研究所
推荐引用方式 GB/T 7714	Gu, QB,Zhao, JX,Fei, J,et al. Modulation of Na+ ,K+ pumping and neurotransmitter uptake by beta-amyloid[J]. NEUROSCIENCE,2004,126(1):61-67.
APA	Gu, QB,Zhao, JX,Fei, J,&Schwarz, W.(2004).Modulation of Na+ ,K+ pumping and neurotransmitter uptake by beta-amyloid.NEUROSCIENCE,126(1),61-67.
MLA	Gu, QB,et al."Modulation of Na+ ,K+ pumping and neurotransmitter uptake by beta-amyloid".NEUROSCIENCE 126.1(2004):61-67.