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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Amyloid β peptide load is correlated with increased β-secretase activity in sporadic Alzheimer's disease patients
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Amyloid β peptide load is correlated with increased β-secretase activity in sporadic Alzheimer's disease patients

机译：偶发性阿尔茨海默氏病患者的淀粉样β肽负荷与β分泌酶活性增加相关

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摘要

Whether elevated β-secretase (BACE) activity is related to plaque formation or amyloid β peptide (Aβ) production in Alzheimer's disease (AD) brains rema|ns inconclusive. Here, we report that we used sandwich enzyme-linked immunoabsorbent assay to quantitate various Aβ species in the frontal cortex of AD brains homogenized in 70% formic acid. We found that most of the Aβspecies detected in rapidly autopsied brains (<3 h) with sporadic AD were Aβ_(1-x) and Aβ_(1-42), as well as Aβ_(x-42). To establish a linkage between Aβ levels and BACE, we examined BACE protein, mRNA expression and enzymatic activity in the same brain region of AD brains. We found that both BACE mRNA and protein expression is elevated in vivo in the frontal cortex. The elevation of BACE enzymatic activity in AD is correlated with brain Aβ_(1-x) and Aβ_(1-42) production. To examine whether BACE elevation was due to mutations in the BACE-coding region, we sequenced the entire ORF region of the BACE gene in these same AD and nondemented patients and performed allelic association analysis. We found no mutations in the ORF of the BACE gene. Moreover, we found few changes of BACE protein and mRNA levels in Swedish mutated amyloid precursor protein-transfected cells. These findings demonstrate correlation between Aβ loads and BACE elevation and also suggest that as a consequence, BACE elevation may lead to increased Aβ production and enhanced deposition of amyloid plaques in sporadic AD patients.
机译：β-分泌酶（BACE）活性升高与阿尔茨海默氏病（AD）大脑中的斑块形成或淀粉样β肽（Aβ）产生有关，尚无定论。在这里，我们报道我们使用了夹心酶联免疫吸附试验来定量在70％甲酸中均质化的AD大脑额叶皮层中的各种Aβ物种。我们发现，在具有偶发性AD的快速尸检大脑（<3小时）中检测到的大多数Aβ种类是Aβ_（1-x）和Aβ_（1-42）以及Aβ_（x-42）。为了建立Aβ水平与BACE之间的联系，我们检查了AD大脑同一大脑区域中的BACE蛋白，mRNA表达和酶活性。我们发现，额叶皮层体内的BACE mRNA和蛋白质表达均升高。 AD中BACE酶活性的升高与大脑Aβ_（1-x）和Aβ_（1-42）的产生有关。为了检查BACE升高是否归因于BACE编码区域的突变，我们对这些AD和非痴呆患者的BACE基因的整个ORF区域进行了测序，并进行了等位基因关联分析。我们没有发现BACE基因的ORF突变。此外，我们发现瑞典突变的淀粉样蛋白前体蛋白转染的细胞中BACE蛋白和mRNA水平几乎没有变化。这些发现证明了Aβ负荷与BACE升高之间的相关性，并且还表明，BACE升高可能导致散发性AD患者Aβ产生增加和淀粉样斑块沉积增加。

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