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Ex vivo (18)O-labeling mass spectrometry identifies a peripheral amyloid β clearance pathway.

Journal article
Authors Erik Portelius
Niklas Mattson
Josef Pannee
Henrik Zetterberg
Magnus Gisslén
Hugo Vanderstichele
Eleni Gkanatsiou
Gabriela A N Crespi
Michael W Parker
Luke A Miles
Johan Gobom
Kaj Blennow
Published in Molecular neurodegeneration
Volume 12
Issue 1
Pages 18
ISSN 1750-1326
Publication year 2017
Published at Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
Institute of Biomedicine, Department of Infectious Medicine
Pages 18
Language en
Links dx.doi.org/10.1186/s13024-017-0152-...
www.ncbi.nlm.nih.gov/entrez/query.f...
Subject categories Neurochemistry

Abstract

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.Using (18)O-labeling mass spectrometry and immune-affinity purification, we examined endogenous proteolytic processing of Aβ in human CSF.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, (18)O-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.(18)O 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.

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