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Soluble amyloid precursor protein alpha and beta in CSF in Alzheimer's disease

Brinkmalm, Gunnar; Brinkmalm, Ann; Bourgeois, Philippe; Persson, Rita; Hansson, Oskar LU ; Portelius, Erik; Mercken, Marc; Andreasson, Ulf; Parent, Stephane and Lipari, Francesco, et al. (2013) In Brain Research1966-01-01+01:00 1513. p.117-126
Abstract
Objective: Cerebral accumulation of amyloid beta (A beta) is a pathological hallmark of Alzheimer's disease (AD). Proteolytic processing of amyloid precursor protein (APP) by alpha- or beta-secretase results in two soluble metabolites, sAPP alpha and sAPP beta, respectively. However, previous data have shown that both alpha- and beta-secretase have multiple cleavage sites. The aim of this study was to characterize the C-termini of sAPP alpha and sAPP beta 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... (More)
Objective: Cerebral accumulation of amyloid beta (A beta) is a pathological hallmark of Alzheimer's disease (AD). Proteolytic processing of amyloid precursor protein (APP) by alpha- or beta-secretase results in two soluble metabolites, sAPP alpha and sAPP beta, respectively. However, previous data have shown that both alpha- and beta-secretase have multiple cleavage sites. The aim of this study was to characterize the C-termini of sAPP alpha and sAPP beta 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 sAPP alpha and sAPP beta 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 sAPP alpha. Results: Four different C-terminal forms of sAPP were identified, sAPP beta-M671, sAPP beta-Y681, sAPP alpha-Q686, and 5APP alpha-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 sAPP alpha and 0.45 for sAPP beta. Conclusion: Using high resolution MS, we show here for the first time that sAPP alpha in CSF ends at Q686 and K687. The findings also support the conclusion from several previous studies that sAPP alpha and sAPP beta levels are unaltered in AD. (C) 2013 Elsevier B.V. All rights reserved. (Less)
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keywords
AlphaLISA immunoassay, Immunoprecipitation, Mass spectrometry, Cerebrospinal fluid, Soluble amyloid precursor protein (sAPP)
in
Brain Research1966-01-01+01:00
volume
1513
pages
117 - 126
publisher
Elsevier
external identifiers
  • wos:000320353200013
  • scopus:84877579899
ISSN
1872-6240
DOI
10.1016/j.brainres.2013.03.019
language
English
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yes
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6a745689-60c6-4c7b-9fc4-ba732908683e (old id 3990293)
date added to LUP
2013-09-02 10:39:47
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2019-02-20 01:49:05
@article{6a745689-60c6-4c7b-9fc4-ba732908683e,
  abstract     = {Objective: Cerebral accumulation of amyloid beta (A beta) is a pathological hallmark of Alzheimer's disease (AD). Proteolytic processing of amyloid precursor protein (APP) by alpha- or beta-secretase results in two soluble metabolites, sAPP alpha and sAPP beta, respectively. However, previous data have shown that both alpha- and beta-secretase have multiple cleavage sites. The aim of this study was to characterize the C-termini of sAPP alpha and sAPP beta 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 sAPP alpha and sAPP beta 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 sAPP alpha. Results: Four different C-terminal forms of sAPP were identified, sAPP beta-M671, sAPP beta-Y681, sAPP alpha-Q686, and 5APP alpha-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 sAPP alpha and 0.45 for sAPP beta. Conclusion: Using high resolution MS, we show here for the first time that sAPP alpha in CSF ends at Q686 and K687. The findings also support the conclusion from several previous studies that sAPP alpha and sAPP beta levels are unaltered in AD. (C) 2013 Elsevier B.V. All rights reserved.},
  author       = {Brinkmalm, Gunnar and Brinkmalm, Ann and Bourgeois, Philippe and Persson, Rita and Hansson, Oskar and Portelius, Erik and Mercken, Marc and Andreasson, Ulf and Parent, Stephane and Lipari, Francesco and Ohrfelt, Annika and Bjerke, Maria and Minthon, Lennart and Zetterberg, Henrik and Blennow, Kaj and Nutu, Magdalena},
  issn         = {1872-6240},
  keyword      = {AlphaLISA immunoassay,Immunoprecipitation,Mass spectrometry,Cerebrospinal fluid,Soluble amyloid precursor protein (sAPP)},
  language     = {eng},
  pages        = {117--126},
  publisher    = {Elsevier},
  series       = {Brain Research1966-01-01+01:00},
  title        = {Soluble amyloid precursor protein alpha and beta in CSF in Alzheimer's disease},
  url          = {http://dx.doi.org/10.1016/j.brainres.2013.03.019},
  volume       = {1513},
  year         = {2013},
}