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

Portelius, Erik ; Mattsson, Niklas LU orcid ; Pannee, Josef ; Zetterberg, Henrik LU ; Gisslén, Magnus ; Vanderstichele, Hugo ; Gkanatsiou, Eleni ; Crespi, Gabriela A N ; Parker, Michael W. and Miles, Luke A. , et al. (2017) In Molecular Neurodegeneration 12(1). p.1-11
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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Amyloid β, Cerebrospinal fluid, Insulin-degrading enzyme, Mass spectrometry, Stable isotope labeling
in
Molecular Neurodegeneration
volume
12
issue
1
article number
18
pages
1 - 11
publisher
BioMed Central (BMC)
external identifiers
  • pmid:28219449
  • wos:000396292300001
  • scopus:85013347521
ISSN
1750-1326
DOI
10.1186/s13024-017-0152-5
language
English
LU publication?
yes
id
94b7af6b-7c20-4fc0-b8b5-8046d7943cbd
date added to LUP
2017-03-06 09:26:09
date last changed
2025-02-04 14:15:32
@article{94b7af6b-7c20-4fc0-b8b5-8046d7943cbd,
  abstract     = {{<p>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.</p>}},
  author       = {{Portelius, Erik and Mattsson, Niklas and Pannee, Josef and Zetterberg, Henrik and Gisslén, Magnus and Vanderstichele, Hugo and Gkanatsiou, Eleni and Crespi, Gabriela A N and Parker, Michael W. and Miles, Luke A. and Gobom, Johan and Blennow, Kaj}},
  issn         = {{1750-1326}},
  keywords     = {{Amyloid β; Cerebrospinal fluid; Insulin-degrading enzyme; Mass spectrometry; Stable isotope labeling}},
  language     = {{eng}},
  month        = {{02}},
  number       = {{1}},
  pages        = {{1--11}},
  publisher    = {{BioMed Central (BMC)}},
  series       = {{Molecular Neurodegeneration}},
  title        = {{Ex vivo 18O-labeling mass spectrometry identifies a peripheral amyloid β clearance pathway}},
  url          = {{http://dx.doi.org/10.1186/s13024-017-0152-5}},
  doi          = {{10.1186/s13024-017-0152-5}},
  volume       = {{12}},
  year         = {{2017}},
}