Liu Wei Wei, Todd Stephen, Coulson David T R, Irvine G Brent, Passmore A Peter, McGuinness Bernadette, McConville Maeve, Craig David, Johnston Janet A
School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, 97 Lisburn Road, Belfast, Northern Ireland, UK.
J Neurochem. 2009 Jan;108(2):341-9. doi: 10.1111/j.1471-4159.2008.05753.x.
Research into the cause of Alzheimer's disease (AD) has identified strong connections to cholesterol. Cholesterol and cholesterol esters can modulate amyloid precursor protein (APP) processing, thus altering production of the Abeta peptides that deposit in cortical amyloid plaques. Processing depends on the encounter between APP and cellular secretases, and is thus subject to the influence of cholesterol-dependent factors including protein trafficking, and distribution between membrane subdomains. We have directly investigated endogenous membrane beta-secretase activity in the presence of a range of membrane cholesterol levels in SH-SY5Y human neuroblastoma cells and human platelets. Membrane cholesterol significantly influenced membrane beta-secretase activity in a biphasic manner, with positive correlations at higher membrane cholesterol levels, and negative correlations at lower membrane cholesterol levels. Platelets from individuals with AD or mild cognitive impairment (n = 172) were significantly more likely to lie within the negative correlation zone than control platelets (n = 171). Pharmacological inhibition of SH-SY5Y beta-secretase activity resulted in increased membrane cholesterol levels. Our findings are consistent with the existence of a homeostatic feedback loop between membrane cholesterol level and membrane beta-secretase activity, and suggest that this regulatory mechanism is disrupted in platelets from individuals with cognitive impairment.
对阿尔茨海默病（AD）病因的研究已确定其与胆固醇存在紧密联系。胆固醇及胆固醇酯可调节淀粉样前体蛋白（APP）的加工过程，进而改变沉积于皮质淀粉样斑块中的β-淀粉样肽的产生。加工过程取决于APP与细胞分泌酶的相互作用，因此会受到包括蛋白质运输及膜亚结构域间分布等胆固醇依赖性因素的影响。我们已在SH-SY5Y人神经母细胞瘤细胞和人血小板中，在一系列膜胆固醇水平存在的情况下，直接研究了内源性膜β-分泌酶的活性。膜胆固醇以双相方式显著影响膜β-分泌酶活性，在较高膜胆固醇水平时呈正相关，在较低膜胆固醇水平时呈负相关。与对照血小板（n = 171）相比，来自AD或轻度认知障碍患者（n = 172）的血小板更有可能处于负相关区域。对SH-SY5Yβ-分泌酶活性的药物抑制导致膜胆固醇水平升高。我们的研究结果与膜胆固醇水平和膜β-分泌酶活性之间存在稳态反馈回路的观点一致，并表明这种调节机制在认知障碍患者的血小板中被破坏。
