BACKGROUND: The mitochondrial enzyme 17β-hydroxysteroid dehydrogenase type 10 (HSD10) is implicated in neurodegenerative disorders, particularly Alzheimer’s disease (AD), through its interplay with the amyloid-β peptide (Aβ). However, its independent pathological role in AD remains unclear. METHODS: To explore the individual effects of HSD10 and amyloid precursor protein (APP) overexpression (including the Aβ42-generating APPSwe/Ind variant), monoclonal HEK293 cell lines were developed. Cellular fitness was evaluated by measuring ATP levels, cell viability, and cytotoxicity measurements under glucose and galactose culture conditions. Mitochondrial metabolic changes were analysed using mitochondrial electron flow measurements in response to various metabolic substrates. HSD10 enzymatic activity was monitored using a fluorogenic probe, and two HSD10 inhibitors were tested for their ability to reduce cytotoxic effects. Statistical significance was determined using appropriate tests as detailed in the methods section. RESULTS: The overexpression of HSD10 or APPSwe/Ind led to mitochondrial dysfunction and reduced viability, particularly under glucose-deprived conditions. HSD10-driven cytotoxicity was linked to its enzymatic activity and associated with impaired TCA cycle function, reduced β-oxidation, and increased oxidative stress. In contrast, APPSwe/Ind overexpression induced Aβ42 production, glucose hypermetabolism, and enhanced β-oxidation. Aβ42 also affected HSD10 activity and further amplified its cytotoxic effects. The benzothiazole-based HSD10 inhibitor 34 restored cell viability under both HSD10 overexpression and Aβ42-rich conditions. CONCLUSIONS: HSD10 and Aβ42 each contribute to mitochondrial impairment via distinct metabolic pathways. These findings established HSD10 as an independent pathological factor in AD and support the potential of HSD10 inhibitors, particularly inhibitor 34, as therapeutic agents targeting mitochondrial dysfunction in AD. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-025-01821-8.

• Klíčová slova
• 17β-hydroxysteroid dehydrogenase type 10, Alzheimer’s disease, Amyloid precursor protein, Amyloid-β peptide, Mitochondria,
• Publikační typ
• časopisecké články MeSH

17β-HSD10 is a mitochondrial enzyme that catalyzes the steroidal oxidation of a hydroxy group to a keto group and, thus, is involved in maintaining steroid homeostasis. The druggability of 17β-HSD10 is related to potential treatment for neurodegenerative diseases, for example, Alzheimer's disease or cancer. Herein, steroidal derivatives with an acidic hemiester substituent at position C-3 on the skeleton were designed, synthesized, and evaluated by using pure recombinant 17β-HSD10 converting 17β-estradiol to estrone. Compounds 22 (IC50 = 6.95 ± 0.35 μM) and 23 (IC50 = 5.59 ± 0.25 μM) were identified as the most potent inhibitors from the series. Compound 23 inhibited 17β-HSD10 activity regardless of the substrate. It was found not cytotoxic toward the HEK-293 cell line and able to inhibit 17β-HSD10 activity also in the cellular environment. Together, these findings support steroidal compounds as promising candidates for further development as 17β-HSD10 inhibitors.

• Publikační typ
• časopisecké články MeSH

Multifunctional mitochondrial enzyme 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10) is a potential drug target for the treatment of various pathologies. The most discussed is the pathology associated with Alzheimer's disease (AD), where 17β-HSD10 overexpression and its interaction with amyloid-β peptide contribute to mitochondrial dysfunction and neuronal stress. In this work, a series of new benzothiazole-derived 17β-HSD10 inhibitors were designed based on the structure-activity relationship analysis of formerly published inhibitors. A set of enzyme-based and cell-based methods were used to evaluate the inhibitory potency of new compounds, their interaction with the enzyme, and their cytotoxicity. Most compounds exhibited significantly a higher inhibitory potential compared to published benzothiazolyl ureas and good target engagement in a cellular environment accompanied by low cytotoxicity. The best hits displayed mixed-type inhibition with half maximal inhibitory concentration (IC50) values in the nanomolar range for the purified enzyme (3-7, 15) and/or low micromolar IC50 values in the cell-based assay (6, 13-16).

• Publikační typ
• časopisecké články MeSH

Increasing life expectancy in modern society is undoubtedly due to improved healthcare, scientific advances in medicine, and the overall healthy lifestyle of the general population. However, this positive trend has led to an increase in the number of older people with a growing need for a sustainable system for the long-term care of this part of the population, which includes social and health services that are essential for a high quality of life. Longevity also brings challenges in the form of a polymorbid geriatric population that places financial pressure on healthcare systems. Regardless, one disease dominates the debate about financial sustainability due to the increasing numbers of people diagnosed, and that is Alzheimer's disease (AD). The presented paper aims to demonstrate the economic burden of social and healthcare services. Data from two regions in the Czech Republic were selected to demonstrate the potential scope of the problem. The future costs connected with AD are calculated by a prediction model, which is based on a population model for predicting the number of people with AD between 2020 and 2070. Based on the presented data from the two regions in the Czech Republic and the prediction model, several trends emerged. There appears to be a significant difference in the annual direct costs per person diagnosed with AD depending on the region in which they reside. This may lead to a significant inequality of the services a person can acquire followed by subsequent social issues that can manifest as a lower quality of life. Furthermore, given the prediction of the growing AD population, the costs expressed in constant prices based on the year 2020 will increase almost threefold during the period 2020-2070. The predicted threefold increase will place additional financial pressure on all stakeholders responsible for social and healthcare services, as the current situation is already challenging.

• Klíčová slova
• Alzheimer’s disease, Czech Republic, costs, prediction model,
• Publikační typ
• časopisecké články MeSH