THE ROLE OF ASTROCYTIC MITOCHONDRIA IN METABOLISM AND INFLAMMATION: IMPLICATIONS FOR ALZHEIMER’S DISEASE

Early hallmarks of Alzheimer's disease (AD) pathology include the disruption of mitochondrial functions and energy balance in the brain (Du et al. 2010, Mosconi 2005, Hoyer et al. 1991). One protein has been hypothesised to be key to this energy balance - 17beta-hydroxysteroid dehydrogenase type 10 (17βHSD10) (Borger et al. 2011). This mitochondrial enzyme has an important role in the break-down of lipids as well as different hormones which modulate brain signalling. 17βHSD10 levels are substantially higher in the brains of AD patients where the enzyme binds A&beta (Yan et al. 1997) and causes significant changes in neuronal functions (Lustbader et al. 2004, Takuma et al. 2005). Since astrocytes are central to neuronal metabolic support, signalling modulation and participate in the inflammatory processes within the brain (Rodríguez-Arellano et al. 2016), they are an important candidate for 17βHSD10-mediated disfunction. In addition, astrocytes surrounding Aβ plaques in brains of AD patients seem to have upregulated 17βHSD10 protein levels (He et al. 2005). Primary mouse astrocytes from cortical, hippocampal and cerebellar regions were cultured and subjected to different pro-inflammatory stimuli, oxidative stress and ischemic conditions. Astrocytic viability and pro-inflammatory changes were assessed and mitochondrial functions were further characterized through seahorse assay. 17βHSD10 protein levels and activity were assessed through Western blot and (-)-CHANA (cyclohexenyl amino naphthalene alcohol) fluorescent activity assay. Results confirm that 17βHSD10 is present and functional in primary mouse astrocytes from different brain regions. Furthermore, we found that 17βHSD10 expression and activity levels vary under different pro-inflammatory and stress conditions relevant to AD, however the changes are not uniform across astrocytes from different brain regions. These changes have further impact on mitochondrial functions and metabolism. These findings suggest that 17βHSD10 could be involved in the differential mitochondrial response of astrocytes to various AD-related insults. This opens yet another avenue in the investigation of region-specific vulnerability to neurodegenerative conditions and related astrocyte-neuron metabolic interactions.