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- Pannee, Josef, 1979, et al.
(författare)
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The amyloid-beta degradation pattern in plasma A possible tool for clinical trials in Alzheimer's disease
- 2014
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Ingår i: Neuroscience Letters. - : Elsevier BV. - 0304-3940 .- 1872-7972. ; 573, s. 7-12
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid beta (A beta) is the main component of plaques, the central neuropathological hallmark in Alzheimer's disease (AD). A beta is derived from the amyloid precursor protein (APP) by beta- and gamma-secretase-mediated cleavages. A large number of A beta peptides are found in cerebrospinal fluid and these peptides are produced in specific metabolic pathways, which are important for diagnosis, in drug development and to explore disease pathogenesis. To investigate whether a similar pattern could be found also in blood samples, an immunoprecipitation (IP) based method for enrichment of A beta peptides from human plasma was developed. The peptides were analyzed using matrix-assisted-laser-desorption/ionization time-of-flight/time-of-flight mass spectrometry for A beta profiling and selected reaction monitoring (SRM) for MS quantification of A beta 1-38, A beta 1-40 and A beta 1-42 using tripe quadrupole MS. Sixteen N- or C-terminally truncated A beta peptides were reproducibly detected in human plasma, of which 11 were verified by tandem MS. In a pilot study including 9 AD patients and 10 controls, where A beta 1-38, A beta 1-40 and A beta 1-42 were quantified using SRM, no AD-associated change in plasma levels of the peptides were observed. Using MS-based measurement techniques, we show that several A beta peptides can be monitored in a single analysis and the developed methods have the potential to be used as a read out in clinical trials of drugs affecting APP processing or A beta homeostasis.
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| 2. |
- Portelius, Erik, 1977, et al.
(författare)
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Altered Cerebrospinal Fluid Levels of Amyloid beta and Amyloid Precursor-Like Protein 1 Peptides in Down's Syndrome
- 2014
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Ingår i: Neuromolecular medicine. - : Springer Science and Business Media LLC. - 1535-1084 .- 1559-1174. ; 16:2, s. 510-516
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Tidskriftsartikel (refereegranskat)abstract
- Down's syndrome (DS) patients develop early Alzheimer's disease pathology with abundant cortical amyloid plaques, likely due to overproduction of the amyloid precursor protein (APP), which subsequently leads to amyloid beta (A beta) aggregation. This is reflected in cerebrospinal fluid (CSF) levels of the 42-amino acid long A beta peptide (A beta 1-42), which are increased in young DS patients and decreases with age. However, it is unclear whether DS also affects other aspects of A beta metabolism, including production of shorter C- and N-terminal truncated A beta peptides, and production of peptides from the amyloid precursor-like protein 1 (APLP1), which is related to APP, and cleaved by the same enzymatic processing machinery. APLP1-derived peptides may be surrogate markers for A beta 1-42 production in the brain. Here, we used hybrid immunoaffinity-mass spectrometry and enzyme-linked immunosorbent assays to monitor several A beta and APLP1 peptides in CSF from DS patients (n = 12) and healthy controls (n = 20). CSF levels of A beta 1-42 and three endogenous peptides derived from APLP1 (APL1 beta 25, APL1 beta 27 and APL1 beta 28) were decreased in DS compared with controls, while a specific A beta peptide, A beta 1-28, was increased in a majority of the DS individuals. This study indicates that DS causes previously unknown specific alterations of APP and APLP1 metabolism.
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