Human cystatin C induces the disaggregation process of selected amyloid beta peptides: a structural and kinetic view.

Autor: Żyła A; Department of Biomedical Physics, Faculty of Physics, Adam Mickiewicz University, Poznań, Poland.; NanoBioMedical Centre, Adam Mickiewicz University, Poznań, Poland., Martel A; Large Scale Structures, ILL Neutrons for Society, Institute Laue-Langevin, Grenoble, France., Jurczak P; Laboratory of Medical Chemistry, Department of Biomedical Chemistry, Faculty of Chemistry, University of Gdańsk, Gdańsk, Poland., Moliński A; Department of Biomedical Physics, Faculty of Physics, Adam Mickiewicz University, Poznań, Poland.; NanoBioMedical Centre, Adam Mickiewicz University, Poznań, Poland., Szymańska A; Laboratory of Medical Chemistry, Department of Biomedical Chemistry, Faculty of Chemistry, University of Gdańsk, Gdańsk, Poland., Kozak M; Department of Biomedical Physics, Faculty of Physics, Adam Mickiewicz University, Poznań, Poland. mkozak@amu.edu.pl.; SOLARIS National Synchrotron Radiation Centre, Jagiellonian University, Kraków, Poland. mkozak@amu.edu.pl.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2023 Nov 27; Vol. 13 (1), pp. 20833. Date of Electronic Publication: 2023 Nov 27.
DOI: 10.1038/s41598-023-47514-w
Abstrakt: Neurodegenerative diseases, such as Alzheimer's disease (AD) and various types of amyloidosis, are incurable; therefore, understanding the mechanisms of amyloid decomposition is crucial to develop an effective drug against them for future therapies. It has been reported that one out of three people over the age of 85 are suffering from dementia as a comorbidity to AD. Amyloid beta (Aβ), the hallmark of AD, transforms structurally from monomers into β-stranded aggregates (fibrils) via multiple oligomeric states. Astrocytes in the central nervous system secrete the human cystatin C protein (HCC) in response to various proteases and cytokines. The codeposition of Aβ and HCC in the brains of patients with AD led to the hypothesis that cystatin C is implicated in the disease process. In this study, we investigate the intermolecular interactions between different atomic structures of fibrils formed by Aβ peptides and HCC to understand the pathological aggregation of these polypeptides into neurotoxic oligomers and then amyloid plaques. To characterize the interactions between Aβ and HCC, we used a complementary approach based on the combination of small-angle neutron scattering analysis, atomic force microscopy and computational modelling, allowing the exploration of the structures of multicomponent protein complexes. We report here an optimized protocol to study that interaction. The results show a dependency of the sequence length of the Aβ peptide on the ability of the associated HCC to disaggregate it.
(© 2023. The Author(s).)
Databáze: MEDLINE
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