有证据表明，γ-分泌酶介导阿尔茨海默病中氧化应激诱导的β-分泌酶表达。
Evidence that gamma-secretase mediates oxidative stress-induced beta-secretase expression in Alzheimer's disease.
机构信息
Laboratory of Neurosciences, National Institute on Aging, Intramural Research Program, Baltimore, MD 21224, USA.
出版信息
Neurobiol Aging. 2010 Jun;31(6):917-25. doi: 10.1016/j.neurobiolaging.2008.07.003. Epub 2008 Aug 8.
Abstract
Beta-secretase (BACE1), an enzyme responsible for the production of amyloid beta-peptide (Abeta), is increased by oxidative stress and is elevated in the brains of patients with sporadic Alzheimer's disease (AD). Here, we show that oxidative stress fails to induce BACE1 expression in presenilin-1 (gamma-secretase)-deficient cells and in normal cells treated with gamma-secretase inhibitors. Oxidative stress-induced beta-secretase activity and sAPPbeta levels were suppressed by gamma-secretase inhibitors. Levels of gamma- and beta-secretase activities were greater in brain tissue samples from AD patients compared to non-demented control subjects, and the elevated BACE1 level in the brains of 3xTgAD mice was reduced by treatment with a gamma-secretase inhibitor. Our findings suggest that gamma-secretase mediates oxidative stress-induced expression of BACE1 resulting in excessive Abeta production in AD.
摘要
β-分泌酶（BACE1）是一种负责产生淀粉样β肽（Abeta）的酶，它会受到氧化应激的增加，并且在散发性阿尔茨海默病（AD）患者的大脑中升高。在这里，我们表明，氧化应激不能诱导早老素 1（γ-分泌酶）缺陷细胞和用 γ-分泌酶抑制剂处理的正常细胞中的 BACE1 表达。γ-分泌酶抑制剂抑制氧化应激诱导的β-分泌酶活性和 sAPPβ 水平。与非痴呆对照受试者相比，AD 患者脑组织样本中的γ-和β-分泌酶活性水平更高，并且用γ-分泌酶抑制剂治疗可降低 3xTgAD 小鼠大脑中的 BACE1 水平升高。我们的研究结果表明，γ-分泌酶介导氧化应激诱导的 BACE1 表达，导致 AD 中 Abeta 的过度产生。
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