Identification of amyloid beta mid-domain fragments in human cerebrospinal fluid

Magnus Rogeberg; Marianne Wettergreen; Lars N G Nilsson; Tormod Fladby

doi:10.1016/j.biochi.2015.03.022

Identification of amyloid beta mid-domain fragments in human cerebrospinal fluid

Biochimie. 2015 Jun:113:86-92. doi: 10.1016/j.biochi.2015.03.022. Epub 2015 Apr 10.

Authors

Magnus Rogeberg¹, Marianne Wettergreen², Lars N G Nilsson³, Tormod Fladby⁴

Affiliations

¹ Department of Neurology, Akershus University Hospital, Lørenskog, Norway; Department of Clinical Molecular Biology (EpiGen), Division of Medicine, Akershus University Hospital and University of Oslo, Norway. Electronic address: magnus.rogeberg@ahus.no.
² Department of Neurology, Akershus University Hospital, Lørenskog, Norway; Department of Clinical Molecular Biology (EpiGen), Division of Medicine, Akershus University Hospital and University of Oslo, Norway.
³ Department of Pharmacology, University of Oslo and Oslo University Hospital, Oslo, Norway.
⁴ Department of Neurology, Akershus University Hospital, Lørenskog, Norway; Department of Neurology, Faculty Division, Akershus University Hospital and University of Oslo, Lørenskog, Norway.

PMID: 25866191
DOI: 10.1016/j.biochi.2015.03.022

Abstract

Amyloid beta (Aβ) is a peptide derived from processing of the membrane bound amyloid precursor protein and is a main constituent in amyloid plaques in Alzheimer's disease (AD). The excess Aβ in AD brain may be caused by altered Aβ metabolism, including reduced enzymatic degradation. Our previous enzymatic study of Aβ degradation revealed that intracellular enzymes produced several truncated Aβ mid-domain fragments. We therefore generated an antibody to enable identification of these anticipated Aβ species in cerebrospinal fluid (CSF). The produced antibody displayed affinity for the Aβ mid-domain region and 36 N-terminally truncated Aβ fragments were precipitated from human CSF and identified by liquid chromatography - mass spectrometry. 31 peptides were truncated from residue 18 up to 23, N-terminal truncation that have not previously been identified in CSF. The results show that the complexity of amyloid beta peptides circulating in the CSF is greater than previously suggested and we also demonstrate that the mid-domain antibody used can serve as an additional tool for mapping a more complete Aβ degradation profile.

Keywords: Alzheimer's disease; Amyloid beta; Cerebrospinal fluid; Immunoprecipitation; Mass spectrometry.

Publication types

Clinical Trial
Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease / cerebrospinal fluid*
Amyloid beta-Peptides / analysis*
Amyloid beta-Peptides / cerebrospinal fluid*
Animals
Antibodies / chemistry*
Female
Humans
Male
Peptide Mapping*
Protein Structure, Tertiary
Rabbits

Substances

Amyloid beta-Peptides
Antibodies