New insights into the 17β-hydroxysteroid dehydrogenase type 10 and amyloid-β 42 derived cytotoxicity relevant to Alzheimer's disease
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00179906%3A_____%2F25%3A10500504" target="_blank" >RIV/00179906:_____/25:10500504 - isvavai.cz</a>
Alternative codes found
RIV/62690094:18470/25:50022505
Result on the web
<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=Rcach2B4Dh" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=Rcach2B4Dh</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1186/s13195-025-01821-8" target="_blank" >10.1186/s13195-025-01821-8</a>
Alternative languages
Result language
angličtina
Original language name
New insights into the 17β-hydroxysteroid dehydrogenase type 10 and amyloid-β 42 derived cytotoxicity relevant to Alzheimer's disease
Original language description
Background The mitochondrial enzyme 17 beta-hydroxysteroid dehydrogenase type 10 (HSD10) is implicated in neurodegenerative disorders, particularly Alzheimer's disease (AD), through its interplay with the amyloid-beta peptide (A beta). 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 A beta 42-generating APP(Swe/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 APP(Swe/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 beta-oxidation, and increased oxidative stress. In contrast, APP(Swe/Ind) overexpression induced A beta 42 production, glucose hypermetabolism, and enhanced beta-oxidation. A beta 42 also affected HSD10 activity and further amplified its cytotoxic effects. The benzothiazole-based HSD10 inhibitor 34 restored cell viability under both HSD10 overexpression and A beta 42-rich conditions. Conclusions HSD10 and A beta 42 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.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10600 - Biological sciences
Result continuities
Project
<a href="/en/project/EH23_021%2F0008439" target="_blank" >EH23_021/0008439: Biomedical Indicators for Personalized Medicine</a><br>
Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2025
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Alzheimer's Research and Therapy
ISSN
1758-9193
e-ISSN
1758-9193
Volume of the periodical
17
Issue of the periodical within the volume
1
Country of publishing house
GB - UNITED KINGDOM
Number of pages
19
Pages from-to
170
UT code for WoS article
001535170700001
EID of the result in the Scopus database
2-s2.0-105011350549