The Mitochondrial Enzyme 17 beta HSD10 Modulates Ischemic and Amyloid-beta-Induced Stress in Primary Mouse Astrocytes

Severe brain metabolic dysfunction and amyloid-beta accumulation are key hallmarks of Alzheimer's disease (AD). While astrocytes contribute to both pathologic mechanisms, the role of their mitochondria, which is essential for signaling and maintenance of these processes, has been largely understudied. The current work provides the first direct evidence that the mitochondrial metabolic switch 17 beta-hydroxysteroid dehydrogenase type 10 (17 beta HSD10) is expressed and active in murine astrocytes from different brain regions. While it is known that this protein is overexpressed in the brains of AD patients, we found that 17 beta HSD10 is also upregulated in astrocytes exposed to amyloidogenic and ischemic stress. Importantly, such catalytic overexpression of 17 beta HSD10 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 (ROS) generation and mitochondrial network alterations during amyloidogenic stress. On the other hand, 17 beta HSD10 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 17 beta HSD10 in multiple neurodegenerative mechanisms.