Mitochondrial function and dysfunction in astrocytes : the role of 17βHSD10 in Alzheimer's disease

Abstract

In an effort to find novel therapeutic targets and biomarkers for Alzheimer’s disease (AD), recent research discovered that astrocytic metabolism is disrupted very early on in the disease and may contribute to disease-specific regional vulnerability to neurodegeneration.

The current work provides evidence that in vitro mouse astrocytes isolated from the cortex, the hippocampus (both affected early in AD progression) and the cerebellum (affected in late stages) are characterised by distinct morphological and metabolic phenotypes. While cortical astrocytes exhibited overall higher metabolic activity, the hippocampal population had the highest glycolytic capacity of all three groups. These disparities were suggested to stem from different capacity for substrate import, utilisation, and metabolic reserve, which in turn determine astrocytic metabolic flexibility. These differences were associated with distinct capability for adaptation to metabolic stress with cerebellar astrocytes being more vulnerable to such conditions. Furthermore, ketone body supplementation was found to have more potent protective effects during nutrient deprivation in cerebellar as compared to other astrocytes. Interestingly, oxidative stress was more detrimental to cortical and hippocampal cells and this is associated with severe alterations in their mitochondrial number and morphology, suggesting that mitochondria may be more involved in astrocytic stress adaptation than previously reported.

The role of the mitochondrial 17β-hydroxysteroid dehydrogenase type 10 (17βHSD10) in astrocytic metabolism is the other main focus of this work. This mitochondrial enzyme is a hypothesised metabolic switch, which directly binds Aβ, exacerbating mitochondrial dysfunction in AD-affected cortical and hippocampal areas. The current work presents the first characterisation of 17βHSD10 function in astrocytes, showing that the protein is an important regulator of mitochondrial respiration and adaptation to metabolic and amyloidogenic stress. Importantly, stress-induced regulation of 17βHSD10 activity and expression showed a region-dependent phenotype, implying that the enzyme may be an important regulator in the reported metabolic heterogeneity of astrocytes. Finally, the impact of the protein on astrocytic function was largely determined by metabolic demand and substrate availability.

In summary, in vitro astrocytes isolated from different brain regions differ in their morphology, metabolic function, and resilience to AD-related stress conditions. 17βHSD10 was identified as an important regulator of their mitochondrial metabolism and region-dependent response to amyloid-induced and metabolic stress. These findings suggest that astrocytic 17βHSD10 could be a central component in the transition between early (amyloid-driven) and late (hypometabolism-driven) neurodegeneration in AD.