Metabolic Profiling of CHO-A beta PP695 Cells Revealed Mitochondrial Dysfunction Prior to Amyloid-beta Pathology and Potential Therapeutic Effects of Both PPAR gamma and PPAR alpha Agonisms for Alzheimer's Disease

摘要

In this study, we performed gas chromatography time-of-flight mass spectrometry (GC-TOFMS)-based extracellular metabolic profiling on A beta PP-transfected CHO cells (CHO-A beta PP695) and its wildtype. Orthogonal partial least squares discriminant analysis (OPLS-DA) was then used to identify discriminant metabolites, which gave clues on the effects of A beta PP transgene on cellular processes. To confirm the hypotheses generated based on the metabolic data, we performed biochemical assays to gather further evidence to support our findings. The OPLS-DA showed a robust differentiation following 24 h of incubation (Q(2)(cum) = 0.884) and 15 discriminant metabolites were identified. In contrast, extracellular A beta(42) was identified to increase significantly in CHO-A beta PP695 only after incubation for 48 h. The observed 24-h metabolic fluxes were associated with increased mitochondrial A beta PP and reduced mitochondrial viabilities, which occurred before extracellular A beta accumulation. We also investigated the therapeutic potential of peroxisome proliferator-activated receptor gamma (PPAR gamma) agonists, namely rosiglitazone (RSG) and pioglitazone (PIO), by employing the same approach to characterize the metabolic profiles of CHOA beta PP695 treated with RSG and PIO, with or without their respective receptor blockers. Treatment with PIO was found to reduce the perturbation of the discriminant metabolites in CHO-A beta PP695 to a larger extent than treatment with RSG. We also attributed the PIO effects on the lowering of A beta(42), and restoration of mitochondrial activity to PPAR gamma and PPAR alpha agonism, respectively. Taken together, PIO was demonstrated to be therapeutically superior to RSG. Our findings provide further insights into early disease stages in this A beta PP model, and support the advancement of PIO in AD therapy.