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Characterization of plasma β‐secretase (BACE1) activity and soluble amyloid precursor proteins as potential biomarkers for Alzheimer's disease
Author(s) -
Wu Guoxin,
Sankaranarayanan Sethu,
Wong Jacky,
Tugusheva Katherine,
Michener Maria S.,
Shi Xiaoping,
Cook Jacquelynn J.,
Simon Adam J.,
Savage Mary J.
Publication year - 2012
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.23122
Subject(s) - amyloid precursor protein secretase , amyloid precursor protein , chemistry , antibody , amyloid (mycology) , cerebrospinal fluid , alzheimer's disease , pharmacodynamics , pharmacology , microbiology and biotechnology , medicine , biochemistry , endocrinology , disease , immunology , biology , pharmacokinetics , inorganic chemistry
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.