Abstract
The nucleus-encoded 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10) regulates cyclophilin D (cypD) in the mitochondrial matrix. CypD regulates opening of mitochondrial permeability transition pores. Both mechanisms may be affected by amyloid β 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 17β-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 17β-HSD10 and cypD in a direct real-time manner and determined, for the first time, the kinetic parameters of the interaction (ka 2.0 × 105 M1s−1, kd 5.8 × 104 s−1, and KD 3.5 × 10–10 M). In McGill-R-Thy1-APP rats compared to controls, levels of 17β-HSD10–cypD complexes were decreased and those of total amyloid β increased. Moreover, the levels of 17β-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 17β-HSD10 to regulate cypD in the mitochondrial matrix probably via direct effects of amyloid β. Levels of 17β-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.
Highlights
The nucleus-encoded mitochondrial matrix protein 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10) is an essential protein operating via multiple enzymatic as well as non-enzymatic functions
Mutual interactions of 17β-HSD10 and amyloid β (Aβ) can be documented by many experiments in vitro [e.g., 2, 7, 9, 13–19], by their co-localization in brain mitochondria of Alzheimer’s disease (AD) patients or of transgenic (Tg) animal models of AD [9] and by detection 17β-HSD10–Aβ complexes occurring in cerebrospinal fluid (CSF) [10, 11]
The main aim of the present study was (i) to determine the kinetic parameters of the interaction between 17βHSD10 and cyclophilin D (cypD) in vitro using the surface plasmon resonance (SPR) biosensor method and (ii) to estimate the levels of 17β-HSD10–cypD complexes formed in vivo either in brain mitochondria isolated from Tg rat model of AD or in CSF samples of AD patients in order to clarify changes occurring in brain mitochondria of individuals with AD in more detail and to evaluate CSF levels of 17β-HSD10–cypD complexes as a promising diagnostic biomarker of AD
Summary
The nucleus-encoded mitochondrial matrix protein 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10) is an essential protein operating via multiple enzymatic as well as non-enzymatic functions. It has been suggested that direct interactions with Parkin protein play a key role in the regulation of levels of mitochondrial 17β-HSD10 and that Parkin overproduction increases 17β-HSD10 levels in the matrix [5]. Double Tg animals overexpressing 17β-HSD10 and mutant human amyloid precursor protein display exaggerated AD-like pathology [7] and suggest that both overexpressed 17βHSD10 and accumulated Aβ in mitochondria could play negative roles in mitochondrial dysfunction seen in AD [17]. Monomeric as well as oligomeric Aβ peptides can bind to 17β-HSD10 with KD about 40–80 nM and the binding results in a distortion of 17β-HSD10 molecule including deformation of D loop and binding pocket for co-factor nicotinamide adenine dinucleotide [2, 7, 14, 15, 18]. It seems that oligomeric Aβ peptides, rather than monomeric Aβ, are able to significantly inhibit enzymatic activity of 17β-HSD10 [2, 7, 18]
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