New insights into the 17β-hydroxysteroid dehydrogenase type 10 and amyloid-β 42 derived cytotoxicity relevant to Alzheimer’s disease

The multifunctional mitochondrial enzyme 17β-hydroxysteroid dehydrogenase type 10 (HSD10) plays an important role in the pathology of several diseases, of which Alzheimer’s disease (AD) is the most debated. HSD10 overexpression and its interplay with amyloid-β peptide (Aβ) are considered a factor contributing to mitochondrial damage and neuronal stress observed in AD patients. This study confirms that individual overexpression of HSD10 or APP (amyloid precursor protein that gives rise to Aβ) leads to cytotoxicity, and both pathological conditions are linked to mitochondrial damage. However, the metabolic changes caused by these two overexpressions significantly differ, particularly in their effect on the tricarboxylic acid cycle and β-oxidation. Furthermore, the enzymatic activity of HSD10 is identified as the primary factor of HSD10 cytotoxicity, which is significantly exacerbated in an Aβ-rich environment and can be partially reversed by HSD10 inhibitors. Notably, a previously published and competitive benzothiazole inhibitor was effective in restoring the viability of HSD10 overexpressing cells alone and in an Aβ-rich environment, implying the potential benefit of HSD10 inhibitors in mitochondrial diseases and/or AD treatment.