The mitochondrial enzyme 17βHSD10 modulates ischemic and amyloid-β-induced stress in primary mouse astrocytes

Funding information: The project is supported by Alzheimer’s Society and RS Macdonald Charitable Trust.Severe brain metabolic dysfunction and amyloid-beta accumulation are key hallmarks of Alzheimer's disease. While astrocytes contribute to both pathological mechanisms, the role of their mitochondria, which is essential for signalling and maintenance of these processes, has been largely understudied. The current work provides the first direct evidence that the mitochondrial metabolic switch 17β-hydroxysteroid dehydrogenase type 10 (17βHSD10) is expressed and active in murine astrocytes from different brain regions. While it is known that this protein is overexpressed in the brains of Alzheimer's disease patients, we found that 17βHSD10 is also upregulated in astrocytes exposed to amyloidogenic and ischemic stress. Importantly, such catalytic overexpression of 17βHSD10 inhibits mitochondrial respiration during increased energy demand. This observation contrasts with what has been found in neuronal and cancer model systems, which suggests astrocyte-specific mechanisms mediated by the protein. Furthermore, the catalytic upregulation of the enzyme exacerbates astrocytic damage, reactive oxygen species generation and mitochondrial network alterations during amyloidogenic stress. On the other hand, 17βHSD10 inhibition through AG18051 counters most of these effects. In conclusion, our data represents novel insights into the role of astrocytic mitochondria in metabolic and amyloidogenic stress with implications of 17βHSD10 in multiple neurodegenerative mechanisms. The current study presents the first direct evidence for the role of enzymatic activity of 17βHSD10 in astrocytes. We report that the protein is involved in the response of cortical astrocytes to stress conditions associated with ischemic stroke and AD. Furthermore, 17βHSD10 regulates astrocytic mitochondrial function, and the effects differ from what has been reported in neurons. These findings contribute to a growing body of evidence showing that astrocytic mitochondria are a key factor in neurodegenerative pathology. Considering the 17βHSD10-targeting therapeutics currently being developed for AD, these findings provide important insight into the role of this target in the cell population which carries out key metabolic support and toxic clearance from the brain.Publisher PDFPeer reviewe