Early derangements of the mitochondrial metabolism in the pre-plaque stage of a transgenic Alzheimer’s disease mouse model

Aims We recently revealed increased metabolic rate and weight differences in female APP23 transgenic mice (APP23), a model for Alzheimer’s disease (AD). Impaired lipid peroxidation and synaptic mitochondrial dysfunction were described in only three-month-old AD mice, which, together with brain glucose hypometabolism, are also used as early indicators for AD. In liver proteomics of pre-plaque stage APP23 mice, we found evidence of potential global mitochondrial dysregulation, which may contribute to AD. Therefore, we hypothesize that APP23 mice generally exhibit aberrations of mitochondrial metabolism.

Methods We measured oxygen consumption rates (OCR) by Seahorse assessing hepatic mitochondrial respiration of 3-months-young and 2-years-old APP23 mice ex vivo. Furthermore, we examined adipocyte lipolytic activity and investigated hepatic gene and OXPHOS protein regulation. OCRs were analyzed regarding sex-specific differences in hepatocytes, stroma-vascular precursor cells (SVC), and ex vivo differentiated adipocytes from young APP23 mice.

Results Basal and maximal OCR in primary hepatocytes of young APP23 mice were elevated, whereas we observed a significant decrease in the entire mitochondrial respiration in old APP23 mice. ER stress genes were upregulated in young and old, while mitochondrial complexes were reduced only in old APP23 mice. Young APP23 females, but not males, showed an enhanced stimulated lipolysis and, consistently, an increased maximal OCR in SVCs and palmitate-stimulated, differentiated adipocytes.

Conclusion We revealed disequilibrated mitochondrial respiration in both hepatocytes and adipocytes of young female APP23 mice even before AD manifestation. Our data suggest that mitochondrial metabolism may also be dysregulated in organs other than the brain, both early and late.

Publikationsverlauf

Artikel online veröffentlicht:
02. Mai 2023