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.

• Keywords
• Alzheimer's disease, Amyloid β, Cerebrospinal fluid, Frontotemporal lobar degeneration, Mitochondrial matrix proteins, Transgenic rat model,
• MeSH
• 17-Hydroxysteroid Dehydrogenases cerebrospinal fluid   metabolism   MeSH
• Alzheimer Disease metabolism   MeSH
• Amyloid beta-Protein Precursor genetics   MeSH
• Kinetics MeSH
• Humans MeSH
• Mitochondria metabolism   MeSH
• Brain metabolism   MeSH
• Peptidyl-Prolyl Isomerase F metabolism   MeSH
• Rats, Transgenic MeSH
• Rats, Wistar MeSH
• Surface Plasmon Resonance MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• 17-Hydroxysteroid Dehydrogenases MeSH
• Amyloid beta-Protein Precursor MeSH
• Peptidyl-Prolyl Isomerase F MeSH

It is well known that misfolded peptides/proteins can play a role in processes of normal ageing and in the pathogenesis of many diseases including Alzheimer's disease. Previously, we evaluated samples of cerebrospinal fluid from patients with Alzheimer's disease and multiple sclerosis by means of thioflavin-T-based fluorescence. We observed attenuated effects of magnetite nanoparticles operated via anti-aggregation actions on peptides/proteins from patients with Alzheimer's disease but not from those with multiple sclerosis when compared to age-related controls. In this study, we have evaluated the in vitro effects of anti-aggregation operating ferrofluid and phytoalexin spirobrassinin in the cerebrospinal fluid of patients with multiple sclerosis and Alzheimer's disease. We have found significant differences in native fluorescence (λ excitation = 440 nm, λ emission = 485 nm) of samples among particular groups (young controls < multiple sclerosis, Alzheimer's disease < old controls). Differences among groups were observed also in thioflavin-T-based fluorescence (young controls = multiple sclerosis < Alzheimer's disease < old controls) and the most marked change from native to thioflavin-T-based fluorescence was found in young controls (28-40 years old people). Both ferrofluid and spirobrassinin evoked drops in thioflavin-T-based fluorescence; however, ferrofluid was more efficient in old controls (54-75 years old people) and spirobrassinin in multiple sclerosis patients, both compared to young controls. The results are discussed especially in relation to aggregated peptides/proteins and liposoluble fluorescent products of lipid peroxidation. Based on the significant effect of spirobrassinin in vitro, we suggest that spirobrassinin may be of therapeutic value in multiple sclerosis.

• MeSH
• Benzothiazoles MeSH
• Chlorides cerebrospinal fluid   MeSH
• Adult MeSH
• Fluorescence MeSH
• Fluorescent Dyes analysis   MeSH
• Middle Aged MeSH
• Humans MeSH
• Multiple Sclerosis cerebrospinal fluid   diagnosis   MeSH
• Aged MeSH
• Spiro Compounds cerebrospinal fluid   MeSH
• Aging cerebrospinal fluid   MeSH
• Thiazoles cerebrospinal fluid   MeSH
• Ferric Compounds cerebrospinal fluid   MeSH
• Ferrous Compounds cerebrospinal fluid   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Benzothiazoles MeSH
• Chlorides MeSH
• ferric chloride MeSH Browser
• ferrous sulfate MeSH Browser
• Fluorescent Dyes MeSH
• phytoalexin spirobrassinin MeSH Browser
• Spiro Compounds MeSH
• Thiazoles MeSH
• thioflavin T MeSH Browser
• Ferric Compounds MeSH
• Ferrous Compounds MeSH

It is suggested that intracellular tau protein (τ), when released extracellularly upon neuron degeneration, could evoke direct toxic effects on the cholinergic neurotransmitter system through muscarinic receptors and thus contribute to the pathogenesis of Alzheimer's disease. In this study, we evaluated the in vitro effects of six naturally occurring monomeric τ isoforms on rat hippocampal synaptosomal choline transporters CHT1 (large transmembrane proteins associated with high-affinity choline transport and vulnerable to actions of amyloid β peptides (Aβ) applied in vitro or in vivo). Some τ isoforms at nM concentrations inhibited choline transport in a dose- and time-dependent saturable manner (352 = 441 > 410 = 383 > 381 = 412) and effects were associated with changes in the Michaelis constant rather than in maximal velocity. Moreover, the actions of τ 352/441 were not influenced by previous depolarisation of synaptosomes or by previous depletion of membrane cholesterol. Specific binding of [3H]hemicholinium-3 was not significantly altered by τ 352/441 at higher nM concentrations. Results of in vitro tests on CHT1 transporters from cholesterol-depleted synaptosomes supported interactions between Aβ 1-40 and τ 352. In addition, we developed surface plasmon resonance biosensors to monitor complexes of Aβ 1-42 and τ 352 using a sandwich detection format. It seems, therefore, that protein τ, similar to Aβ peptides, can contribute to the pathogenesis of Alzheimer's disease through its actions on CHT1 transporters. However, the interaction mechanisms are quite different (τ probably exerts its effects through direct interactions of microtubule binding repeats with extracellular portions of the CHT1 protein without influencing the choline recognition site, Aβ rather through lipid rafts in the surrounding membranes). An N-terminal insert of τ is not necessary but the N-terminal projection domain plays a role. The developed biosensor will be used to detect Aβ-τ complexes in cerebrospinal fluid in order to evaluate them as prospective biomarkers of Alzheimer's disease.

• MeSH
• Amyloid beta-Peptides metabolism   MeSH
• Hippocampus metabolism   MeSH
• Rats MeSH
• Rats, Wistar MeSH
• Surface Plasmon Resonance MeSH
• Cation Transport Proteins metabolism   MeSH
• tau Proteins metabolism   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Amyloid beta-Peptides MeSH
• CHT1 protein, rat MeSH Browser
• Cation Transport Proteins MeSH
• tau Proteins MeSH