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本文引用的文献

1
Building gamma-secretase: the bits and pieces.构建γ-分泌酶：各个组成部分
J Cell Sci. 2008 Feb 15;121(Pt 4):413-20. doi: 10.1242/jcs.015255.
2
Presenilin: running with scissors in the membrane.早老素：在膜中拿着剪刀奔跑。
Cell. 2007 Oct 19;131(2):215-21. doi: 10.1016/j.cell.2007.10.012.
3
Amyloid precursor protein regulates brain apolipoprotein E and cholesterol metabolism through lipoprotein receptor LRP1.淀粉样前体蛋白通过脂蛋白受体LRP1调节脑载脂蛋白E和胆固醇代谢。
Neuron. 2007 Oct 4;56(1):66-78. doi: 10.1016/j.neuron.2007.08.008.
4
The secreted beta-amyloid precursor protein ectodomain APPs alpha is sufficient to rescue the anatomical, behavioral, and electrophysiological abnormalities of APP-deficient mice.分泌型β-淀粉样前体蛋白胞外结构域APPsα足以挽救APP缺陷小鼠的解剖学、行为学和电生理学异常。
J Neurosci. 2007 Jul 18;27(29):7817-26. doi: 10.1523/JNEUROSCI.1026-07.2007.
5
Presenilin diversifies its portfolio.早老素使其产品组合多样化。
Trends Genet. 2007 Mar;23(3):140-50. doi: 10.1016/j.tig.2007.01.008. Epub 2007 Feb 5.
6
GGA1 is expressed in the human brain and affects the generation of amyloid beta-peptide.GGA1在人类大脑中表达，并影响β淀粉样肽的生成。
J Neurosci. 2006 Dec 6;26(49):12838-46. doi: 10.1523/JNEUROSCI.1982-06.2006.
7
The nucleation growth and reversibility of Amyloid-beta deposition in vivo.体内β-淀粉样蛋白沉积的成核生长与可逆性
J Alzheimers Dis. 2006 Nov;10(2-3):291-301. doi: 10.3233/jad-2006-102-313.
8
Mean age-of-onset of familial alzheimer disease caused by presenilin mutations correlates with both increased Abeta42 and decreased Abeta40.由早老素突变引起的家族性阿尔茨海默病的平均发病年龄与β淀粉样蛋白42增加和β淀粉样蛋白40减少均相关。
Hum Mutat. 2006 Jul;27(7):686-95. doi: 10.1002/humu.20336.
9
Presenilin/gamma-secretase activity regulates protein clearance from the endocytic recycling compartment.早老素/γ-分泌酶活性调节内吞循环区室中的蛋白质清除。
FASEB J. 2006 Jun;20(8):1176-8. doi: 10.1096/fj.05-5531fje. Epub 2006 Apr 27.
10
Amyloid precursor protein and Notch intracellular domains are generated after transport of their precursors to the cell surface.淀粉样前体蛋白和Notch细胞内结构域在其前体转运至细胞表面后产生。
Traffic. 2006 Apr;7(4):408-15. doi: 10.1111/j.1600-0854.2006.00396.x.

γ-分泌酶功能丧失会损害脂蛋白颗粒的内吞作用和膜胆固醇稳态。

Loss of gamma-secretase function impairs endocytosis of lipoprotein particles and membrane cholesterol homeostasis.

作者信息

Tamboli Irfan Y, Prager Kai, Thal Dietmar R, Thelen Karin M, Dewachter Ilse, Pietrzik Claus U, St George-Hyslop Peter, Sisodia Sangram S, De Strooper Bart, Heneka Michael T, Filippov Mikhail A, Müller Ulrike, van Leuven Fred, Lütjohann Dieter, Walter Jochen

机构信息

Department of Neurology, University of Bonn, 53127 Bonn, Germany.

出版信息

J Neurosci. 2008 Nov 12;28(46):12097-106. doi: 10.1523/JNEUROSCI.2635-08.2008.

DOI:10.1523/JNEUROSCI.2635-08.2008
PMID:19005074
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6671640/
Abstract

Presenilins (PSs) are components of the gamma-secretase complex that mediates intramembranous cleavage of type I membrane proteins. We show that gamma-secretase is involved in the regulation of cellular lipoprotein uptake. Loss of gamma-secretase function decreased endocytosis of low-density lipoprotein (LDL) receptor. The decreased uptake of lipoproteins led to upregulation of cellular cholesterol biosynthesis by increased expression of CYP51 and enhanced metabolism of lanosterol. Genetic deletion of PS1 or transgenic expression of PS1 mutants that cause early-onset Alzheimer's disease led to accumulation of gamma-secretase substrates and mistargeting of adaptor proteins that regulate endocytosis of the LDL receptor. Consistent with decreased endocytosis of these receptors, PS1 mutant mice have elevated levels of apolipoprotein E in the brain. Thus, these data demonstrate a functional link between two major genetic factors that cause early-onset and late-onset Alzheimer's disease.

摘要

早老素（PSs）是γ-分泌酶复合物的组成成分，该复合物介导I型膜蛋白的膜内裂解。我们发现γ-分泌酶参与细胞脂蛋白摄取的调节。γ-分泌酶功能丧失会降低低密度脂蛋白（LDL）受体的内吞作用。脂蛋白摄取减少导致细胞胆固醇生物合成上调，这是通过CYP51表达增加和羊毛甾醇代谢增强实现的。PS1基因缺失或导致早发性阿尔茨海默病的PS1突变体的转基因表达导致γ-分泌酶底物的积累以及调节LDL受体内吞作用的衔接蛋白靶向错误。与这些受体的内吞作用降低一致，PS1突变小鼠大脑中的载脂蛋白E水平升高。因此，这些数据证明了导致早发性和晚发性阿尔茨海默病的两个主要遗传因素之间的功能联系。