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- Frankel, R., et al.
(författare)
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Autocatalytic amplification of Alzheimer-associated A beta 42 peptide aggregation in human cerebrospinal fluid
- 2019
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Ingår i: Communications Biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 2
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease is linked to amyloid beta (A beta) peptide aggregation in the brain, and a detailed understanding of the molecular mechanism of A beta aggregation may lead to improved diagnostics and therapeutics. While previous studies have been performed in pure buffer, we approach the mechanism in vivo using cerebrospinal fluid (CSF). We investigated the aggregation mechanism of A beta 42 in human CSF through kinetic experiments at several A beta 42 monomer concentrations (0.8-10 mu M). The data were subjected to global kinetic analysis and found consistent with an aggregation mechanism involving secondary nucleation of monomers on the fibril surface. A mechanism only including primary nucleation was ruled out. We find that the aggregation process is composed of the same microscopic steps in CSF as in pure buffer, but the rate constant of secondary nucleation is decreased. Most importantly, the autocatalytic amplification of aggregate number through catalysis on the fibril surface is prevalent also in CSF.
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| 6. |
- Ljung, R., et al.
(författare)
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Platelet-associated IgG in childhood idiopathic thrombocytopenic purpura : measurements on intact and solubilized platelets and after gammaglobulin treatment
- 1986
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Ingår i: Scandinavian Journal of Haematology. - : Wiley. - 0036-553X. ; 36:4, s. 402-407
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Tidskriftsartikel (refereegranskat)abstract
- An immunoradiometric assay was developed for determining platelet-associated IgG (PAIgG) both on intact and solubilized platelets. In 20 healthy subjects PAIgG was 0.28 ± 0.20 ng/106 platelets and 2.2 ± 1.1 ng/106 platelets on intact and on solubilized platelets, respectively. 13 children with acute ITP all had increased concentrations of PAIgG, but no correlation was found between the severity of thrombocytopenia and PAIgG concentrations, either on intact or on solubilized platelets. Neither was there any correlation of the increase in PAIgG between intact and solubilized preparations. 3 out of 4 children who received high-dose i.v. gammaglobulin showed a concomitant normalization of the platelet count and of the PAIgG concentration both on intact and lyzed platelets. The remaining child did not respond to gammaglobulin and continued to have abnormal PAIgG.
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| 7. |
- Meisl, Georg, et al.
(författare)
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Differences in nucleation behavior underlie the contrasting aggregation kinetics of the Aβ40 and Aβ42 peptides.
- 2014
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Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 111:26, s. 9384-9389
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Tidskriftsartikel (refereegranskat)abstract
- The two major forms of the amyloid-beta (Aβ) peptide found in plaques in patients suffering from Alzheimer's disease, Aβ40 and Aβ42, only differ by two amino acids in the C-terminal region, yet they display markedly different aggregation behavior. The origins of these differences have remained challenging to connect to specific molecular-level processes underlying the aggregation reaction. In this paper we use a general strategy to apply the conventional workflow of chemical kinetics to the aggregation of the Aβ40 peptide to identify the differences between Aβ40 and Aβ42 in terms of the microscopic determinants of the aggregation reaction. Our results reveal that the major source of aggregates in the case of Aβ40 is a fibril-catalyzed nucleation process, the multistep nature of which is evident through its saturation behavior. Moreover, our results show that the significant differences in the observed behavior of the two proteins originate not simply from a uniform increase in all microscopic rates for Aβ42 compared with Aβ40, but rather are due to a shift of more than one order of magnitude in the relative importance of primary nucleation versus fibril-catalyzed secondary nucleation processes. This analysis sheds light on the microscopic determinants of the aggregation behavior of the principal forms of Aβ and outlines a general approach toward achieving an understanding at the molecular level of the aberrant deposition of insoluble peptides in neurodegenerative disorders.
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