Effect of Different Phospholipids on α-Secretase Activity in the Non-Amyloidogenic Pathway of Alzheimer's Disease.
Effect of Different Phospholipids on α-Secretase Activity in the Non-Amyloidogenic Pathway of Alzheimer's Disease.
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DOI：
10.3390/ijms14035879
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发表时间：
2013-03-13
影响因子：
5.6
通讯作者：
Hartmann T
中科院分区：
文献类型：
--
作者：
Grimm MO;Haupenthal VJ;Rothhaar TL;Zimmer VC;Grösgen S;Hundsdörfer B;Lehmann J;Grimm HS;Hartmann T
阿尔茨海默病（Alzheimer's disease，AD）的特征是β-和γ-分泌酶对淀粉样前体蛋白（amyloid precursor protein，APP）进行蛋白水解加工后产生的β-淀粉样肽（amyloid-β peptide，Aβ）在细胞外蓄积。当α-分泌酶在Aβ结构域内裂解APP引起初始胞外域脱落时，Aβ生成受到抑制。因此，α-分泌酶活性的增加是AD治疗的有吸引力的治疗靶点。APP和APP裂解分泌酶都是跨膜蛋白，因此提出局部膜脂质组成影响APP加工。虽然一些研究集中在γ-分泌酶，膜脂微环境对α-分泌酶的影响知之甚少。本文系统地研究了脂肪酸（FA）酰基链长（10：0、12：0、14：0、16：0、18：0、20：0、22：0、24：0）、膜极性脂头基（磷脂酰胆碱、磷脂酰乙醇胺、磷脂酰丝氨酸）、饱和度和FA双键位置对α-分泌酶活性的影响。我们发现，α-分泌酶的活性显着升高，在存在短链长度的脂肪酸和多不饱和脂肪酸的存在下，而在磷脂头基的变化，以及双键的位置，对α-分泌酶的活性几乎没有或没有影响。总体而言，我们的研究表明，局部脂质膜组成可以影响α-分泌酶活性，并可能对AD有有益作用。
Alzheimer’s disease (AD) is characterized by extracellular accumulation of amyloid-β peptide (Aβ), generated by proteolytic processing of the amyloid precursor protein (APP) by β- and γ-secretase. Aβ generation is inhibited when the initial ectodomain shedding is caused by α-secretase, cleaving APP within the Aβ domain. Therefore, an increase in α-secretase activity is an attractive therapeutic target for AD treatment. APP and the APP-cleaving secretases are all transmembrane proteins, thus local membrane lipid composition is proposed to influence APP processing. Although several studies have focused on γ-secretase, the effect of the membrane lipid microenvironment on α-secretase is poorly understood. In the present study, we systematically investigated the effect of fatty acid (FA) acyl chain length (10:0, 12:0, 14:0, 16:0, 18:0, 20:0, 22:0, 24:0), membrane polar lipid headgroup (phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine), saturation grade and the FA double-bond position on α-secretase activity. We found that α-secretase activity is significantly elevated in the presence of FAs with short chain length and in the presence of polyunsaturated FAs, whereas variations in the phospholipid headgroups, as well as the double-bond position, have little or no effect on α-secretase activity. Overall, our study shows that local lipid membrane composition can influence α-secretase activity and might have beneficial effects for AD.
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DOI：
10.1083/jcb.200207113
发表时间：
2003-01-06
期刊：
The Journal of cell biology
影响因子：
--
作者：
Ehehalt R;Keller P;Haass C;Thiele C;Simons K
通讯作者：
Simons K
DOI：
10.1016/j.plefa.2009.05.015
发表时间：
2009-08
期刊：
Prostaglandins, leukotrienes, and essential fatty acids
影响因子：
--
作者：
Cole GM;Ma QL;Frautschy SA
通讯作者：
Frautschy SA
影响因子：
4.8
作者：
Buxbaum, JD;Liu, KN;Black, RA
通讯作者：
Black, RA
影响因子：
4.1
作者：
Grimm, Marcus O. W.;Groesgen, Sven;Hartmann, Tobias
通讯作者：
Hartmann, Tobias
影响因子：
4.7
作者：
Hartmann, Tobias;Kuchenbecker, Johannna;Grimm, Marcus O. W.
通讯作者：
Grimm, Marcus O. W.