Characterization of plasma β-secretase (BACE1) activity and soluble amyloid precursor proteins as potential biomarkers for Alzheimer’s disease
Abstract
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.
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CSF BACE1 concentration and activity have good diagnostic performance in discriminating AD dementia, MCI, and cognitively healthy individuals.
“During the past 15 years, a few human in vivo studies reported good diagnostic performance of CSF BACE1 concentration (supposed to reflect gene expression levels) and activity in discriminating among patients with AD dementia, patients with MCI, and cognitively healthy individuals (79–85).”
From The β-Secretase BACE1 in Alzheimer’s Disease (2021) · cites this paper as [82]
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References 49 · Cited by 68
- Authors
- Wu, G., Sankaranarayanan, S., Wong, J., Tugusheva, K., Michener, M. S., Shi, X., Cook, J. J., Simon, A. J., & Savage, M. J.
- Affiliations
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- Corresponding author
- Wu, Guoxin
- Venue
- Journal of Neuroscience Research
- Publisher
- Wiley
- Published
- 2012-09-18
- Volume
- 90
- Issue
- 12
- Pages
- 2247-2258
- ISSN
- 0360-4012 (ISSN-L)
- 1097-4547
- OpenAlex
- W1980636621
- Cited by
- 68
- References
- 49
- Citations by year
- 2025: 6 · 2024: 2 · 2023: 5 · 2022: 4 · 2021: 6 · 2020: 3 · 2019: 6 · 2018: 7 · 2017: 3 · 2016: 3 · 2015: 8 · 2014: 3 · 2013: 12
- FWCI
- 4.93
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neuroscience Research (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Keywords
- Alzheimer's disease, sAPPα, sAPPβ, plasma biomarkers, total tau, secretase inhibitors, pharmacodynamic biomarkers, immunodepletion, APP knockout mice, rhesus monkeys
- MeSH terms
- Aged, Alzheimer Disease, Animals, Female, Humans, Immunohistochemistry, Macaca mulatta, Male, Mice, Inbred C57BL, Mice, Transgenic, Middle Aged, Peptide Fragments, Sensitivity and Specificity, Sulfonamides, Biomarkers, Amyloid beta-Peptides, Aspartic Acid Endopeptidases, Amyloid beta-Protein Precursor, Mice, Knockout, Mice, Amyloid Precursor Protein Secretases
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