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- Portelius, Erik, 1977, et al.
(författare)
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Distinct cerebrospinal fluid amyloid beta peptide signatures in sporadic and PSEN1 A431E-associated familial Alzheimer's disease.
- 2010
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Ingår i: Molecular neurodegeneration. - : Springer Science and Business Media LLC. - 1750-1326. ; 5:2
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Alzheimer's disease (AD) is associated with deposition of amyloid beta (Abeta) in the brain, which is reflected by low concentration of the Abeta1-42 peptide in the cerebrospinal fluid (CSF). There are at least 15 additional Abeta peptides in human CSF and their relative abundance pattern is thought to reflect the production and degradation of Abeta. Here, we test the hypothesis that AD is characterized by a specific CSF Abeta 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 Abeta 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 Abeta1-42 and high levels of Abeta1-16 distinguished SAD patients and FAD mutation carriers from healthy controls and depressed patients. SAD and FAD were characterized by similar changes in Abeta1-42 and Abeta1-16, but FAD mutation carriers exhibited very low levels of Abeta1-37, Abeta1-38 and Abeta1-39. CONCLUSION: SAD patients and PSEN1 A431E mutation carriers are characterized by aberrant CSF Abeta isoform patterns that hold clinically relevant diagnostic information. PSEN1 A431E mutation carriers exhibit low levels of Abeta1-37, Abeta1-38 and Abeta1-39; 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.
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| 2. |
- Sjölander, Annica, 1969, et al.
(författare)
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BACE1 gene variants do not influence BACE1 activity, levels of APP or Abeta isoforms in CSF in Alzheimer's disease.
- 2010
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Ingår i: Molecular neurodegeneration. - : Springer Science and Business Media LLC. - 1750-1326. ; 5:1
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Tidskriftsartikel (refereegranskat)abstract
- ABSTRACT: The BACE1 gene encodes the beta-site APP-cleaving enzyme 1 and has been associated with Alzheimer's disease (AD). BACE1 is the most important beta-secretase responsible for the generation of Alzheimer-associated amyloid beta-proteins (Abeta) and may play a role in the amyloidogenic process in AD. We hypothesized that BACE1 gene variants might influence BACE1 activity or other markers for APP metabolism in the cerebrospinal fluid (CSF) and thereby contribute to the development of AD. We genotyped a Swedish sample of 269 AD patients for the rs638405 single nucleotide polymorphism (SNP) in the BACE1 gene and correlated genotype data to a broad range of amyloid-related biomarkers in CSF, including BACE1 activity, levels of Abeta40, Abeta42, alpha- and beta-cleaved soluble APP (alpha-sAPP and beta-sAPP), as well as markers for Alzheimer-type axonal degeneration, i.e., total-tau and phospho-tau181. Gene variants of BACE1 were neither associated with amyloid-related biomarkers, nor with markers for axonal degeneration in AD.
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| 3. |
- Zetterberg, Madeleine, 1969, et al.
(författare)
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Ubiquitin carboxy-terminal hydrolase L1 (UCHL1) S18Y polymorphism in Alzheimer's disease.
- 2010
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Ingår i: Molecular neurodegeneration. - : Springer Science and Business Media LLC. - 1750-1326. ; 5
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Tidskriftsartikel (refereegranskat)abstract
- ABSTRACT: Alzheimer's disease (AD) is characterized by protein aggregates, i.e. senile plaques and neurofibrillary tangles. The ubiquitin-proteasome system has been proposed a role in proteolytic removal of these protein aggregates. Ubiquitin carboxy-terminal hydrolase L1 (UCHL1) is a de-ubiquitinating enzyme with important functions in recycling of ubiquitin. The S18Y polymorphism of the UCHL1 gene confers protection against Parkinson's disease. In this study, the genotype and allele frequencies of the UCHL1 S18Y polymorphism were investigated in 452 AD patients and 234 control subjects, recruited from four memory clinics in Sweden. Using a binary logistic regression model including UCHL1 allele A and APOE epsilon4 allele positivity, age and sex as covariates with AD diagnosis as dependent variable, an adjusted OR of 0.82 ([95% CI 0.55-1.24], P = 0.35) was obtained for a positive UCHL1 allele A carrier status. The present study thus do not support a protective effect of the UCHL1 S18Y polymorphism against AD.
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