Metabolic profiling of CHO-AßPP695 cells revealed mitochondrial dysfunction prior to amyloid-ß pathology and potential therapeutic effects of both PPARγ and PPARα Agonisms for Alzheimer's disease.
J Alzheimers Dis
; 44(1): 215-31, 2015.
Article
em En
| MEDLINE
| ID: mdl-25201780
ABSTRACT
In this study, we performed gas chromatography time-of-flight mass spectrometry (GC-TOFMS)-based extracellular metabolic profiling on AßPP-transfected CHO cells (CHO-AßPP695) 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 AßPP 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 (Q2(cum) = 0.884) and 15 discriminant metabolites were identified. In contrast, extracellular Aß42 was identified to increase significantly in CHO-AßPP695 only after incubation for 48 h. The observed 24-h metabolic fluxes were associated with increased mitochondrial AßPP and reduced mitochondrial viabilities, which occurred before extracellular Aß accumulation. We also investigated the therapeutic potential of peroxisome proliferator-activated receptor gamma (PPARγ) agonists, namely rosiglitazone (RSG) and pioglitazone (PIO), by employing the same approach to characterize the metabolic profiles of CHO-AßPP695 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-AßPP695 to a larger extent than treatment with RSG. We also attributed the PIO effects on the lowering of Aß42, and restoration of mitochondrial activity to PPARγ and PPARα agonism, respectively. Taken together, PIO was demonstrated to be therapeutically superior to RSG. Our findings provide further insights into early disease stages in this AßPP model, and support the advancement of PIO in AD therapy.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Precursor de Proteína beta-Amiloide
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Tiazolidinedionas
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PPAR alfa
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PPAR gama
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Revista:
J Alzheimers Dis
Assunto da revista:
GERIATRIA
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NEUROLOGIA
Ano de publicação:
2015
Tipo de documento:
Article
País de afiliação:
Reino Unido
País de publicação:
HOLANDA
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HOLLAND
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NETHERLANDS
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NL
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PAISES BAJOS
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THE NETHERLANDS