Soluble amyloid precursor protein α and β in CSF in Alzheimer's disease

Brain Res. 2013 Jun 4;1513:117-26. doi: 10.1016/j.brainres.2013.03.019. Epub 2013 Mar 27.

Abstract

Objective: Cerebral accumulation of amyloid β (Aβ) is a pathological hallmark of Alzheimer's disease (AD). Proteolytic processing of amyloid precursor protein (APP) by α- or β-secretase results in two soluble metabolites, sAPPα and sAPPβ, respectively. However, previous data have shown that both α- and β-secretase have multiple cleavage sites. The aim of this study was to characterize the C-termini of sAPPα and sAPPβ in cerebrospinal fluid (CSF) by mass spectrometry (MS) and to evaluate whether different combinations of these fragments better separate between AD patients and controls by comparing two different sAPP immunoassays.

Methods: Using immunoprecipitation and high resolution MS, the APP species present in CSF were investigated. CSF levels of sAPPα and sAPPβ from patients with AD (n=43) and from non-demented controls (n=44) were measured using AlphaLISA and MSD immunoassays that employ different antibodies for C-terminal recognition of sAPPα.

Results: Four different C-terminal forms of sAPP were identified, sAPPβ-M671, sAPPβ-Y681, sAPPα-Q686, and sAPPα-K687 (APP770 numbering). Neither immunoassay for the sAPP species could separate the two patient groups. The correlation (R(2)) between the two immunoassays was 0.41 for sAPPα and 0.45 for sAPPβ.

Conclusion: Using high resolution MS, we show here for the first time that sAPPα in CSF ends at Q686 and K687. The findings also support the conclusion from several previous studies that sAPPα and sAPPβ levels are unaltered in AD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / cerebrospinal fluid*
  • Amyloid beta-Peptides / cerebrospinal fluid*
  • Amyloid beta-Protein Precursor / cerebrospinal fluid*
  • Chromatography, Liquid
  • Female
  • Humans
  • Immunoprecipitation
  • Male
  • Middle Aged
  • Peptide Fragments / cerebrospinal fluid*
  • Tandem Mass Spectrometry
  • tau Proteins / cerebrospinal fluid

Substances

  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Peptide Fragments
  • amyloid beta-protein (1-42)
  • tau Proteins