期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2004
卷号：101
期号：10
页码：3632-3637
DOI：10.1073/pnas.0205689101
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Whether elevated {beta}-secretase (BACE) activity is related to plaque formation or amyloid {beta} peptide (A{beta}) production in Alzheimer's disease (AD) brains remains inconclusive. Here, we report that we used sandwich enzyme-linked immunoabsorbent assay to quantitate various A{beta} species in the frontal cortex of AD brains homogenized in 70% formic acid. We found that most of the A{beta} species detected in rapidly autopsied brains (<3 h) with sporadic AD were A{beta}1-x and A{beta}1-42, as well as A{beta}x-42. To establish a linkage between A{beta} 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 A{beta}1-x and A{beta}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 A{beta} loads and BACE elevation and also suggest that as a consequence, BACE elevation may lead to increased A{beta} production and enhanced deposition of amyloid plaques in sporadic AD patients.
