Interactions of 17β-Hydroxysteroid Dehydrogenase Type 10 and Cyclophilin D in Alzheimer's Disease

0524502 - ÚFE 2021 RIV US eng J - Journal Article
Krištofíková, Z. - Špringer, Tomáš - Gedeonová, Erika - Hofmannová, A. - Říčný, J. - Hromádková, L. - Vyhnálek, M. - Laczó, J. - Nikolai, T. - Hort, J. - Petrásek, Tomáš - Stuchlík, Aleš - Valeš, K. - Klaschka, Jan - Homola, Jiří
Interactions of 17β-Hydroxysteroid Dehydrogenase Type 10 and Cyclophilin D in Alzheimer's Disease.
Neurochemical Research. Roč. 45, č. 4 (2020), s. 915-927. ISSN 0364-3190. E-ISSN 1573-6903
R&D Projects: GA MZd(CZ) NV16-27611A
Institutional support: RVO:67985882 ; RVO:67985823 ; RVO:67985807
Keywords : Cerebrospinal fluid * Mitochondrial matrix proteins * Amyloid β * Transgenic rat model * Alzheimer's disease * Frontotemporal lobar degeneration
OECD category: Biochemistry and molecular biology; Biochemistry and molecular biology (FGU-C); Biochemistry and molecular biology (UIVT-O)
Impact factor: 3.996, year: 2020
Method of publishing: Open access
https://link.springer.com/content/pdf/10.1007/s11064-020-02970-y.pdf

The nucleus-encoded 17 beta-hydroxysteroid dehydrogenase type 10 (17 beta-HSD10) regulates cyclophilin D (cypD) in the mitochondrial matrix. CypD regulates opening of mitochondrial permeability transition pores. Both mechanisms may be affected by amyloid beta peptides accumulated in mitochondria in Alzheimer's disease (AD). In order to clarify changes occurring in brain mitochondria, we evaluated interactions of both mitochondrial proteins in vitro (by surface plasmon resonance biosensor) and detected levels of various complexes of 17 beta-HSD10 formed in vivo (by sandwich ELISA) in brain mitochondria isolated from the transgenic animal model of AD (homozygous McGill-R-Thy1-APP rats) and in cerebrospinal fluid samples of AD patients. By surface plasmon resonance biosensor, we observed the interaction of 17 beta-HSD10 and cypD in a direct real-time manner and determined, for the first time, the kinetic parameters of the interaction (k(a) 2.0 x 10(5) M(1)s(-1), k(d) 5.8 x 10(4) s(-1), and K-D 3.5 x 10(-10) M). In McGill-R-Thy1-APP rats compared to controls, levels of 17 beta-HSD10-cypD complexes were decreased and those of total amyloid beta increased. Moreover, the levels of 17 beta-HSD10-cypD complexes were decreased in cerebrospinal fluid of individuals with AD (in mild cognitive impairment as well as dementia stages) or with Frontotemporal lobar degeneration (FTLD) compared to cognitively normal controls (the sensitivity of the complexes to AD dementia was 92.9%, that to FTLD 73.8%, the specificity to AD dementia equaled 91.7% in a comparison with the controls but only 26.2% with FTLD). Our results demonstrate the weakened ability of 17 beta-HSD10 to regulate cypD in the mitochondrial matrix probably via direct effects of amyloid beta. Levels of 17 beta-HSD10-cypD complexes in cerebrospinal fluid seem to be the very sensitive indicator of mitochondrial dysfunction observed in neurodegeneration but unfortunately not specific to AD pathology. We do not recommend it as the new biomarker of AD
Permanent Link: http://hdl.handle.net/11104/0308856