Title: Ex vivo O-18-labeling mass spectrometry identifies a peripheral amyloid beta clearance pathway
Authors: Portelius, E
Mattsson, N
Pannee, J
Zetterberg, H
Gisslen, M
Vanderstichele, H
Gkanatsiou, E
Crespi, GAN
Parker, MW
Miles, LA
Gobom, J
Blennow, K
Issue Year: 2017
Series Mol. Neurodegener.:
Abstract Background: Proteolytic degradation of amyloid beta (A beta) peptides has been intensely studied due to the central role of A beta in Alzheimer's disease (AD) pathogenesis. While several enzymes have been shown to degrade A beta peptides, the main pathway of A beta degradation in vivo is unknown. Cerebrospinal fluid (CSF) A beta 42 is reduced in AD, reflecting aggregation and deposition in the brain, but low CSF A beta 42 is, for unknown reasons, also found in some inflammatory brain disorders such as bacterial meningitis. Method: Using O-18-labeling mass spectrometry and immune-affinity purification, we examined endogenous proteolytic processing of A beta in human CSF. Results: The A beta peptide profile was stable in CSF samples from healthy controls but in CSF samples from patients with bacterial meningitis, showing increased leukocyte cell count, O-18-labeling mass spectrometry identified proteolytic activities degrading A beta into several short fragments, including abundant A beta 1-19 and 1-20. After antibiotic treatment, no degradation of A beta 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-A beta antibody solanezumab was found to inhibit insulin-degrading enzyme-mediated A beta degradation. Conclusion: O-18 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 A beta in the mid-domain of the peptide, and could be inhibited by a recombinant version of the mid-domain anti-A beta antibody solanezumab.
URI: https://publications.svi.edu.au/publications/6304
Other Identifiers 10.1186/s13024-017-0152-5
Publication type Article