Acetyl-CoA is a central metabolite crucial for energy production and the activity of the citric acid cycle (TCA) to support oxidative phosphorylation (OXPHOS) in brain cells. In Alzheimer’s disease (AD), a neurodegenerative disorder that affects millions per year, one of the prominent characteristics is a reduction in glucose uptake, resulting in a diminished level of acetyl-CoA. Along with decreased acetyl-CoA levels, AD also presents reduced histone acetylation, one of the main downstream targets of acetyl-CoA, subsequently resulting in a downregulation of gene transcription. We have shown that mild inhibition of mitochondrial complex I with tricyclicpyrone compound CP2 induces the adaptive stress response, activating multiple neuroprotective mechanisms in brain cells. One of these mechanisms includes increased glucose uptake and utilization. The aim of this project is to test whether CP2-dependent improvement in glucose uptake results in an increased level of acetyl-CoA and an improved transcription of genes involved in cognition. Using SH-SY5Y neuroblastoma cells expressing human mutant APP protein with Swedish mutation (APPswe), we first assessed the downstream targets of acetyl-CoA (H3K27-acetylation and H3K27-tri-methylation) using Western Blot analysis. Cells were treated for 4 and 24 hours to determine whether epigenetic modifications sensitive to acetyl-CoA levels occurred after CP2 treatment at 0.25 μM or 2.5 μM. In APPswe cells, 24 hours of CP2 treatment increased acetylation 30%, restoring levels to the observed level in control cells. In contrast, tri-methylation showed nearly a 20% decrease after 24 hours of CP2 treatment in APPswe cells. Direct measurements of acetyl-CoA mirrored the increased acetylation in APPswe cells with a 30% increase in acetyl-CoA levels after 24 hours of CP2 treatment. These findings suggest that CP2-dependent increase in glucose uptake and utilization in APPswe cells results in an increase of both whole cell acetyl-CoA levels and an improvement in gene expression associated with cognition via histone acetylation. These preliminary results will be validated in future studies.
