Amyloid β peptide load is correlated with increased β-secretase activity in sporadic Alzheimer's disease patients

Rena Li, Kristina Lindholm, Li Bang Yang, Xu Yue, Martin Citron, Riqiang Yan, Thomas Beach, Lucia Sue, Marwan Sebbagh, Huaibin Cai, Philip Wong, Donald Price, Yong Shen

Research output: Contribution to journalArticle

Abstract

Whether elevated β-secretase (BACE) activity is related to plaque formation or amyloid β peptide (Aβ) production in Alzheimer's disease (AD) brains remains 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 Aβ species detected in rapidly autopsied brains (<3 h) with sporadic AD were Aβ1-x and Aβ1-42, as well as Aβx-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 Aβ1-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.

Original languageEnglish (US)
Pages (from-to)3632-3637
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume101
Issue number10
DOIs
StatePublished - Mar 9 2004

ASJC Scopus subject areas

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