Metabolic reprogramming and the role of the BCAT protein - implications for type 2 diabetes and Alzheimer's disease

Introduction: Oxidative stress and impaired homeostasis are key features of type 2 diabetes mellitus, which is comorbid with Alzheimer’s disease. Dysregulation of the branched-chain aminotransferase protein, which is overexpressed in AD, is suggested to be involved in metabolic reprogramming, thus impacting on oxidative stress and protein misfolding and aggregation. However, the precise changes in cellular health resulting from BCAT dysregulation remain unclear. Methods and Results: Using SH-SY5Y neuronal models and a combination of metabolomics, biochemical and molecular techniques, we showed that changes in the expression of BCATc affect metabolite load and impair enzymes of glycolysis therefore acting as a glycolytic regulator, with changes in its redox status shifting its binding abilities to enzymes of the TCA cycle and oxidative phosphorylation. In addition, BCATc dysregulation led to impairment of proteins of the antioxidant system and an increase in ROS generation, disruption of the autophagy pathway and increased expression of toxic protein aggregates such as amyloid β and hyperphosphorylated tau. Conclusion: These results demonstrate that BCATc dysregulation leads to metabolic reprogramming and the redox environment of the cell has a key role in these outcomes. Although further studies are required to evaluate whether BCATc overexpression occurs as a result of chronic levels of branched-chain amino acids or otherwise, this study showed that its expression levels are key in the regulation of energy pathways. This in turn impacts on oxidative stress and clearance mechanisms such as autophagy, ultimately contributing to protein aggregation and cellular death as observed in AD

Distribution of the branched-chain α-ketoacid dehydrogenase complex E1α subunit and glutamate dehydrogenase in the human brain and their role in neuro-metabolism

© 2017 Glutamate is the major excitatory neurotransmitter of the central nervous system, with the branched-chain amino acids (BCAAs) acting as key nitrogen donors for de novo glutamate synthesis. Despite the importance of these major metabolites, their metabolic pathway in the human brain is still not well characterised. The metabolic pathways that influence the metabolism of BCAAs have been well characterised in rat models. However, the expression of key proteins such as the branched-chain α-ketoacid dehydrogenase (BCKD) complex and glutamate dehydrogenase isozymes (GDH) in the human brain is still not well characterised. We have used specific antibodies to these proteins to analyse their distribution within the human brain and report, for the first time, that the E1α subunit of the BCKD is located in both neurons and vascular endothelial cells. We also demonstrate that GDH is localised to astrocytes, although vascular immunolabelling does occur. The labelling of GDH was most intense in astrocytes adjacent to the hippocampus, in keeping with glutamatergic neurotransmission in this region. GDH was also present in astrocyte processes abutting vascular endothelial cells. Previously, we demonstrated that the branched-chain aminotransferase (hBCAT) proteins were most abundant in vascular cells (hBCATm) and neurons (hBCATc). Present findings are further evidence that BCAAs are metabolised within both the vasculature and neurons in the human brain. We suggest that GDH, hBCAT and the BCKD proteins operate in conjunction with astrocytic glutamate transporters and glutamine synthetase to regulate the availability of glutamate. This has important implications given that the dysregulation of glutamate metabolism, leading to glutamate excitotoxicity, is an important contributor to the pathogenesis of several neurodegenerative conditions such as Alzheimer's disease