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Distinct cerebrospinal fluid amyloid beta peptide signatures in sporadic and PSEN1 A431E-associated familial Alzheimer's disease

Portelius, Erik ; Andreasson, Ulf ; Ringman, John M. ; Buerger, Katharina ; Daborg, Jonny ; Buchhave, Peder LU ; Hansson, Oskar LU orcid ; Harmsen, Andreas ; Gustavsson, Mikael K. and Hanse, Eric , et al. (2010) In Molecular Neurodegeneration 5.
Abstract
Background: Alzheimer's disease (AD) is associated with deposition of amyloid beta (A beta) in the brain, which is reflected by low concentration of the A beta 1-42 peptide in the cerebrospinal fluid (CSF). There are at least 15 additional A beta peptides in human CSF and their relative abundance pattern is thought to reflect the production and degradation of A beta. Here, we test the hypothesis that AD is characterized by a specific CSF A beta isoform pattern that is distinct when comparing sporadic AD (SAD) and familial AD (FAD) due to different mechanisms underlying brain amyloid pathology in the two disease groups. Results: We measured A beta isoform concentrations in CSF from 18 patients with SAD, 7 carriers of the FAD-associated... (More)
Background: Alzheimer's disease (AD) is associated with deposition of amyloid beta (A beta) in the brain, which is reflected by low concentration of the A beta 1-42 peptide in the cerebrospinal fluid (CSF). There are at least 15 additional A beta peptides in human CSF and their relative abundance pattern is thought to reflect the production and degradation of A beta. Here, we test the hypothesis that AD is characterized by a specific CSF A beta isoform pattern that is distinct when comparing sporadic AD (SAD) and familial AD (FAD) due to different mechanisms underlying brain amyloid pathology in the two disease groups. Results: We measured A beta isoform concentrations in CSF from 18 patients with SAD, 7 carriers of the FAD-associated presenilin 1 (PSEN1) A431E mutation, 17 healthy controls and 6 patients with depression using immunoprecipitation-mass spectrometry. Low CSF levels of A beta 1-42 and high levels of A beta 1-16 distinguished SAD patients and FAD mutation carriers from healthy controls and depressed patients. SAD and FAD were characterized by similar changes in A beta 1-42 and A beta 1-16, but FAD mutation carriers exhibited very low levels of A beta 1-37, A beta 1-38 and A beta 1-39. Conclusion: SAD patients and PSEN1 A431E mutation carriers are characterized by aberrant CSF A beta isoform patterns that hold clinically relevant diagnostic information. PSEN1 A431E mutation carriers exhibit low levels of A beta 1-37, A beta 1-38 and A beta 1-39; fragments that are normally produced by gamma-secretase, suggesting that the PSEN1 A431E mutation modulates gamma-secretase cleavage site preference in a disease-promoting manner. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Molecular Neurodegeneration
volume
5
publisher
BioMed Central (BMC)
external identifiers
  • wos:000274401500001
  • scopus:76749167709
  • pmid:20145736
ISSN
1750-1326
DOI
10.1186/1750-1326-5-2
language
English
LU publication?
yes
id
08063002-848a-4b81-98ff-7cfa73ef8c9d (old id 1570039)
date added to LUP
2016-04-01 13:04:50
date last changed
2022-05-19 17:31:49
@article{08063002-848a-4b81-98ff-7cfa73ef8c9d,
  abstract     = {{Background: Alzheimer's disease (AD) is associated with deposition of amyloid beta (A beta) in the brain, which is reflected by low concentration of the A beta 1-42 peptide in the cerebrospinal fluid (CSF). There are at least 15 additional A beta peptides in human CSF and their relative abundance pattern is thought to reflect the production and degradation of A beta. Here, we test the hypothesis that AD is characterized by a specific CSF A beta isoform pattern that is distinct when comparing sporadic AD (SAD) and familial AD (FAD) due to different mechanisms underlying brain amyloid pathology in the two disease groups. Results: We measured A beta isoform concentrations in CSF from 18 patients with SAD, 7 carriers of the FAD-associated presenilin 1 (PSEN1) A431E mutation, 17 healthy controls and 6 patients with depression using immunoprecipitation-mass spectrometry. Low CSF levels of A beta 1-42 and high levels of A beta 1-16 distinguished SAD patients and FAD mutation carriers from healthy controls and depressed patients. SAD and FAD were characterized by similar changes in A beta 1-42 and A beta 1-16, but FAD mutation carriers exhibited very low levels of A beta 1-37, A beta 1-38 and A beta 1-39. Conclusion: SAD patients and PSEN1 A431E mutation carriers are characterized by aberrant CSF A beta isoform patterns that hold clinically relevant diagnostic information. PSEN1 A431E mutation carriers exhibit low levels of A beta 1-37, A beta 1-38 and A beta 1-39; fragments that are normally produced by gamma-secretase, suggesting that the PSEN1 A431E mutation modulates gamma-secretase cleavage site preference in a disease-promoting manner.}},
  author       = {{Portelius, Erik and Andreasson, Ulf and Ringman, John M. and Buerger, Katharina and Daborg, Jonny and Buchhave, Peder and Hansson, Oskar and Harmsen, Andreas and Gustavsson, Mikael K. and Hanse, Eric and Galasko, Douglas and Hampel, Harald and Blennow, Kaj and Zetterberg, Henrik}},
  issn         = {{1750-1326}},
  language     = {{eng}},
  publisher    = {{BioMed Central (BMC)}},
  series       = {{Molecular Neurodegeneration}},
  title        = {{Distinct cerebrospinal fluid amyloid beta peptide signatures in sporadic and PSEN1 A431E-associated familial Alzheimer's disease}},
  url          = {{http://dx.doi.org/10.1186/1750-1326-5-2}},
  doi          = {{10.1186/1750-1326-5-2}},
  volume       = {{5}},
  year         = {{2010}},
}