Portelius, E;
Mattsson, N;
Pannee, J;
Zetterberg, H;
Gisslen, M;
Vanderstichele, H;
Gkanatsiou, E;
... Blennow, K; + view all
(2017)
Ex vivo O-18-labeling mass spectrometry identifies a peripheral amyloid beta clearance pathway.
Molecular Neurodegeneration
, 12
, Article 18. 10.1186/s13024-017-0152-5.
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Abstract
BACKGROUND: Proteolytic degradation of amyloid β (Aβ) peptides has been intensely studied due to the central role of Aβ in Alzheimer’s disease (AD) pathogenesis. While several enzymes have been shown to degrade Aβ peptides, the main pathway of Aβ degradation in vivo is unknown. Cerebrospinal fluid (CSF) Aβ42 is reduced in AD, reflecting aggregation and deposition in the brain, but low CSF Aβ42 is, for unknown reasons, also found in some inflammatory brain disorders such as bacterial meningitis. METHOD: Using 18O-labeling mass spectrometry and immune-affinity purification, we examined endogenous proteolytic processing of Aβ in human CSF. RESULTS: The Aβ peptide profile was stable in CSF samples from healthy controls but in CSF samples from patients with bacterial meningitis, showing increased leukocyte cell count, 18O-labeling mass spectrometry identified proteolytic activities degrading Aβ into several short fragments, including abundant Aβ1–19 and 1–20. After antibiotic treatment, no degradation of Aβ was detected. In vitro experiments located the source of the proteolytic activity to blood components, including leukocytes and erythrocytes, with insulin-degrading enzyme as the likely protease. A recombinant version of the mid-domain anti-Aβ antibody solanezumab was found to inhibit insulin-degrading enzyme-mediated Aβ degradation. CONCLUSION: 18O labeling-mass spectrometry can be used to detect endogenous proteolytic activity in human CSF. Using this technique, we found an enzymatic activity that was identified as insulin-degrading enzyme that cleaves Aβ in the mid-domain of the peptide, and could be inhibited by a recombinant version of the mid-domain anti-Aβ antibody solanezumab.
| Type: | Article |
|---|---|
| Title: | Ex vivo O-18-labeling mass spectrometry identifies a peripheral amyloid beta clearance pathway |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1186/s13024-017-0152-5 |
| Publisher version: | http://doi.org/10.1186/s13024-017-0152-5 |
| Additional information: | © The Author(s). 2017. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
| Keywords: | Science & Technology, Life Sciences & Biomedicine, Neurosciences, Neurosciences & Neurology, Amyloid beta, Mass spectrometry, Stable isotope labeling, Cerebrospinal fluid, Insulin-degrading enzyme, INSULIN-DEGRADING ENZYME, MODERATE ALZHEIMER-DISEASE, PLASMA A-BETA, CEREBROSPINAL-FLUID, MULTIPLE-SCLEROSIS, BACE1 ACTIVITY, MOUSE MODEL, IN-VIVO, PROTEIN, BRAIN |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1550019 |
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