| 1. |
- Andreasson, Ulf, 1968, et al.
(författare)
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Aspects of beta-amyloid as a biomarker for Alzheimer's disease
- 2007
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Ingår i: Biomarkers in Medicine. - : Future Medicine Ltd. - 1752-0363 .- 1752-0371. ; 1:1, s. 59-78
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Forskningsöversikt (refereegranskat)abstract
- Alzheimer’s disease is an age-related neurodegenerative disorder that results in progressive cognitive impairment and death. The accumulation of β-amyloid (Aβ) in specific brain regions is believed by many to represent the earliest event in the pathogenesis of the disease. Here, we review the key aspects of Aβ as a biomarker for Alzheimer’s disease, including the pathogenicity of Aβ, the possible biological functions of its precursor protein, the Aβ metabolism and homeostasis, the diagnostic performance of different Aβ assays in different settings and the potential usefulness of Aβ as a surrogate marker for treatment efficacy in clinical trials of novel Aβ-targeting drugs against Alzheimer’s disease.
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| 2. |
- Brinkmalm-Westman, Ann, 1966, et al.
(författare)
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Proteomics/peptidomics tools to find CSF biomarkers for neurodegenerative diseases.
- 2009
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Ingår i: Frontiers in bioscience : a journal and virtual library. - : IMR Press. - 1093-4715. ; 14, s. 1793-806
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Forskningsöversikt (refereegranskat)abstract
- Neurodegenerative diseases are characterized by premature neuronal loss in specific brain regions. During the past decades our knowledge on molecular mechanisms underlying neurodegeneration has increased immensely and resulted in promising drug candidates that might slow down or even stop the neuronal loss. These advances have put a strong focus on the development of diagnostic tools for early or pre-clinical detection of the disorders. In this review we discuss our experience in the field of neuroproteomics/peptidomics, with special focus on biomarker discovery studies that have been performed on CSF samples from well-defined patient and control populations.
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| 3. |
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| 4. |
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| 5. |
- Philipson, Ola, et al.
(författare)
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A highly insoluble state of Abeta similar to that of Alzheimer's disease brain is found in Arctic APP transgenic mice.
- 2009
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Ingår i: Neurobiology of aging. - : Elsevier BV. - 1558-1497 .- 0197-4580. ; 30:9, s. 1393-405
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid-beta (Abeta) is a major drug target in Alzheimer's disease. Here, we demonstrate that deposited Abeta is SDS insoluble in tgAPP-ArcSwe, a transgenic mouse model harboring the Arctic (E693G) and Swedish (KM670/671NL) APP mutations. Formic acid was needed to extract the majority of deposited Abeta in both tgAPP-ArcSwe and Alzheimer's disease brain, but not in a commonly used type of mouse model with the Swedish mutation alone. Interestingly, the insoluble state of Arctic Abeta was determined early on and did not gradually evolve with time. In tgAPP-ArcSwe, Abeta plaques displayed a patchy morphology with bundles of Abeta fibrils, whereas amyloid cores in tgAPP-Swe were circular with radiating fibrils. Amyloid was more densely stacked in tgAPP-ArcSwe, as demonstrated with a conformation sensitive probe. A reduced increase in plasma Abeta was observed following acute administration of an Abeta antibody in tgAPP-ArcSwe, results that might imply reduced brain to plasma Abeta efflux. TgAPP-ArcSwe, with its insoluble state of deposited Abeta, could serve as a complementary model to better predict the outcome of clinical trials.
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| 6. |
- Portelius, Erik, 1977, et al.
(författare)
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An Alzheimer's disease-specific beta-amyloid fragment signature in cerebrospinal fluid.
- 2006
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Ingår i: Neuroscience letters. - : Elsevier BV. - 0304-3940. ; 409:3, s. 215-9
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Tidskriftsartikel (refereegranskat)abstract
- Pathogenic events in Alzheimer's disease (AD) involve an imbalance between the production and clearance of the neurotoxic beta-amyloid peptide (Abeta), especially the 42 amino acid peptide Abeta1-42. While much is known about the production of Abeta1-42, many questions remain about how the peptide is degraded. To investigate the degradation pattern, we developed a method based on immunoprecipitation combined with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry that determines the Abeta degradation fragment pattern in cerebrospinal fluid (CSF). We found in total 18 C-terminally and 2 N-terminally truncated Abeta peptides and preliminary data indicated that there were differences in the detected Abeta relative abundance pattern between AD and healthy controls. Here, we provide direct evidence that an Abeta fragment signature consisting of Abeta1-16, Abeta1-33, Abeta1-39, and Abeta1-42 in CSF distinguishes sporadic AD patients from non-demented controls with an overall accuracy of 86%.
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| 7. |
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| 8. |
- Portelius, Erik, 1977, et al.
(författare)
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Characterization of tau in cerebrospinal fluid using mass spectrometry.
- 2008
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Ingår i: Journal of proteome research. - : American Chemical Society (ACS). - 1535-3893 .- 1535-3907. ; 7:5, s. 2114-20
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Tidskriftsartikel (refereegranskat)abstract
- The neurodegenerative disorder Alzheimer's disease (AD) is the most common cause of dementia in the elderly. The presence of neurofibrillary tangles, consisting of hyperphosphorylated tau protein, is one of the major neuropathologic characteristics of the disease, making this protein an attractive biomarker for AD and a possible target for therapy. Here, we describe an optimized immunoprecipitation mass spectrometry method that enables, for the first time, detailed characterization of tau in human cerebrospinal fluid. The identities of putative tau fragments were confirmed using nanoflow liquid chromatography and tandem mass spectrometry. Nineteen tryptic fragments of tau were detected, of which 16 are found in all tau isoforms while 3 represented unique tau isoforms. These results pave the way for clinical CSF studies on the tauopathies.
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| 9. |
- Portelius, Erik, 1977, et al.
(författare)
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Determination of beta-amyloid peptide signatures in cerebrospinal fluid using immunoprecipitation-mass spectrometry.
- 2006
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Ingår i: Journal of proteome research. - : American Chemical Society (ACS). - 1535-3893 .- 1535-3907. ; 5:4, s. 1010-6
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Tidskriftsartikel (refereegranskat)abstract
- Early pathogenic events in Alzheimer's disease (AD) involve increased production and/or reduced clearance of beta-amyloid (Abeta), especially the 42 amino acid fragment Abeta1-42. The Abeta1-42 peptide is generated through cleavage of the amyloid precursor protein by beta- and gamma-secretase and is catabolised by a variety of proteolytic enzymes such as insulin-degrading enzyme and neprilysin. Here, we describe a method that employs immunoprecipitation combined with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry to determine the pattern of C-terminally truncated Abeta peptides in cerebrospinal fluid (CSF). Using antibodies coupled to magnetic beads, we have detected 18 C-terminally and 2 N-terminally truncated Abeta peptides in CSF. By determining the identity and profile of the truncated Abeta peptides, more insight may be gained about differences in the metabolism and structural properties of Abeta in AD. Finally, the Abeta fragment signatures may prove useful as a diagnostic test for AD.
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| 10. |
- Portelius, Erik, 1977, et al.
(författare)
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Effects of gamma-Secretase Inhibition on the Amyloid beta Isoform Pattern in a Mouse Model of Alzheimer's Disease.
- 2009
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Ingår i: Neuro-degenerative diseases. - : S. Karger AG. - 1660-2862 .- 1660-2854. ; 6:5-6
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Tidskriftsartikel (refereegranskat)abstract
- Background:Accumulation of amyloid beta (Abeta) in the brain is believed to represent one of the earliest events in the Alzheimer disease process. Abeta is generated from amyloid precursor protein after sequential cleavage by beta- and gamma-secretase. Alternatively, alpha-secretase cleaves within the Abeta sequence, thus, precluding the formation of Abeta. A lot of research has focused on Abeta production, while less is known about the non-amyloidogenic pathway. We have previously shown that Abeta is present in human cerebrospinal fluid (CSF) as several shorter C-terminal truncated isoforms (e.g. Abeta1-15 and Abeta1-16), and that the levels of these shorter isoforms are elevated in media from cells that have been treated with gamma-secretase inhibitors. Objective:To explore the effect of N-[N-(3,5-difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butyl ester (DAPT), a gamma-secretase-inhibitor, treatment on the Abeta isoform pattern in brain tissue and CSF from Tg2576 mice. Methods: Immunoprecipitation using the anti-Abeta antibodies 6E10 and 4G8 was combined with either matrix-assisted laser desorption/ionization time-of-flight mass spectrometry or nanoflow liquid chromatography and tandem mass spectrometry. Results: All fragments longer than and including Abeta1-17 displayed a tendency towards decreased levels upon gamma-secretase inhibition, whereas Abeta1-15 and Abeta1-16 indicated slightly elevated levels during treatment. Conclusion: These data suggest that Abeta1-15 and Abeta1-16 may be generated through a third metabolic pathway independent of gamma-secretase, and that these Abeta isoforms may serve as biomarkers for secretase inhibitor treatment.
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