Characterization of plasma β-secretase (BACE1) activity and soluble amyloid precursor proteins as potential biomarkers for Alzheimer's disease
Article first published online: 18 SEP 2012
Copyright © 2012 Wiley Periodicals, Inc.
Journal of Neuroscience Research
Volume 90, Issue 12, pages 2247–2258, December 2012
How to Cite
Wu, G., Sankaranarayanan, S., Wong, J., Tugusheva, K., Michener, M. S., Shi, X., Cook, J. J., Simon, A. J. and Savage, M. J. (2012), Characterization of plasma β-secretase (BACE1) activity and soluble amyloid precursor proteins as potential biomarkers for Alzheimer's disease. J. Neurosci. Res., 90: 2247–2258. doi: 10.1002/jnr.23122
- Issue published online: 18 OCT 2012
- Article first published online: 18 SEP 2012
- Manuscript Accepted: 16 JUL 2012
- Manuscript Revised: 8 JUL 2012
- Manuscript Received: 31 MAY 2012
- Alzheimer's disease
Reduction in cerebrospinal fluid (CSF) amyloid β42 (Aβ42) and elevation in total tau and phospho-thr181 tau consistently differentiate between Alzheimer's disease (AD) and age-matched control subjects. In contrast, CSF β-site APP-cleaving enzyme activity (BACE1) and soluble amyloid precursor proteins α and β (sAPPα and sAPPβ) are without consistent patterns in AD subjects. Plasma sampling is much easier, with fewer side effects, and is readily applied in primary care centers, so we have developed and validated novel plasma BACE activity, sAPPβ, and sAPPα assays and investigated their ability to distinguish AD from age-matched controls. Plasma BACE activity assay was sensitive and specific, with signal being immunodepleted with a specific BACE1 antibody and inhibited with a BACE1-specific inhibitor. Plasma sAPPβ and sAPPα assays were specific, with signal diluting linearly, immunodepleted with specific antibodies, and at background levels in APP knockout mice. In rhesus monkeys, BACE1 but not γ-secretase inhibitor led to significant lowering of plasma sAPPβ with concurrent elevation of plasma sAPPα. AD subjects showed a significant increase in plasma BACE1 activity, sAPPβ, sAPPα, and Aβ42 (P < 0.001) compared with age-matched controls. In conclusion, plasma BACE activity and sAPP endpoints provide novel investigative biomarkers for AD diagnosis and potential pharmacodynamic biomarkers for secretase inhibitor studies. © 2012 Wiley Periodicals, Inc.