Ghribi Othman, Larsen Brian, Schrag Matthew, Herman Mary M
Department of Pharmacology, Physiology and Therapeutics, University of North Dakota School of Medicine and Health Sciences, 501 North Columbia Road, Grand Forks, 58202, USA.
Exp Neurol. 2006 Aug;200(2):460-7. doi: 10.1016/j.expneurol.2006.03.019. Epub 2006 May 11.
Epidemiological, cellular, and animal studies suggest that abnormalities in cholesterol metabolism may contribute to the etiology of Alzheimer's disease by increasing the generation of beta-amyloid (Abeta). However, the mechanism by which cholesterol increases Abeta levels is not fully understood. In the present study, we demonstrate that feeding rabbits with 1% cholesterol for 7 months causes an increase in cholesterol content in neurons. High cholesterol content in neurons is accompanied by an increase in the level of BACE1, the enzyme that initially cleaves beta-amyloid precursor protein to generate Abeta, causing the accumulation of Abeta1-42 peptide. These effects correlate with the phosphorylation of tau and the activation of extracellular signal-regulated protein kinase (ERK). Our data suggest that excessive cholesterol content in neurons, following long-term dietary cholesterol, may underlie the increase in BACE1 and Abeta levels. Increased Abeta levels may in turn trigger the phosphorylation of tau by activating ERK.
流行病学、细胞和动物研究表明，胆固醇代谢异常可能通过增加β-淀粉样蛋白（Aβ）的生成而导致阿尔茨海默病的病因。然而，胆固醇增加Aβ水平的机制尚未完全了解。在本研究中，我们证明给兔子喂食1%胆固醇7个月会导致神经元中胆固醇含量增加。神经元中高胆固醇含量伴随着β-分泌酶1（BACE1）水平的增加，该酶最初切割β-淀粉样前体蛋白以生成Aβ，导致Aβ1-42肽的积累。这些效应与tau蛋白的磷酸化和细胞外信号调节蛋白激酶（ERK）的激活相关。我们的数据表明，长期饮食胆固醇后神经元中过量的胆固醇含量可能是BACE1和Aβ水平增加的基础。Aβ水平的增加可能反过来通过激活ERK触发tau蛋白的磷酸化。
