title: Rosiglitazone activation of PPARγ-dependent pathways is neuroprotective in human neural stem cells against amyloid-beta-induced mitochondrial dysfunction and oxidative stress.
abstract: Neuronal cell impairment, such as that induced by amyloid-beta (Aβ) protein, is a process with limited therapeutic interventions and often leads to long-term neurodegeneration common in disorders such as Alzheimer's disease. Interestingly, peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-activated nuclear receptor whose ligands control many physiological and pathologic processes, and may be neuroprotective. We hypothesized that rosiglitazone, a PPARγ agonist, would prevent Aβ-mediated effects in human neural stem cells (hNSCs). Here, we show that rosiglitazone reverses, via PPARγ-dependent downregulation of caspase 3 and 9 activity, the Aβ-mediated decreases in hNSC cell viability. In addition, Aβ decreases hNSC messenger RNA (mRNA) levels of 2 neuroprotective factors (Bcl-2 and CREB), but co-treatment with rosiglitazone significantly rescues these effects. Rosiglitazone co-treated hNSCs also showed significantly increased mitochondrial function (reflected by levels of adenosine triphosphate and Mit mass), and PPARγ-dependent mRNA upregulation of PGC1α and mitochondrial genes (nuclear respiratory factor-1 and Tfam). Furthermore, hNSCs co-treated with rosiglitazone were significantly rescued from Aβ-induced oxidative stress and correlates with reversal of the Aβ-induced mRNA decrease in oxidative defense genes (superoxide dismutase 1, superoxide dismutase 2, and glutathione peroxidase 1). Taken together, these novel findings show that rosiglitazone-induced activation of PPARγ-dependent signaling rescues Aβ-mediated toxicity in hNSCs and provide evidence supporting a neuroprotective role for PPARγ activating drugs in Aβ-related diseases such as Alzheimer's disease.
authors.affiliation: Department of Life Science, College of Science and Engineering, Fu Jen Catholic University, New Taipei City, Taiwan. Electronic address: cmcphd@gmail.com.
authors.forename: Ming-Chang
authors.initials: MC
authors.lastname: Chiang
authors.affiliation: Division of Cancer Biology & Genetics, Departments of Pathology & Molecular Medicine and Biomedical & Molecular Sciences, Cancer Research Institute, Queen's University, Kingston, Ontario, Canada.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Nicol
authors.affiliation: Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Tao Yuan, Taiwan.
authors.forename: Yi-Chuan
authors.initials: YC
authors.lastname: Cheng
authors.affiliation: Graduate Institute of Biotechnology, Chinese Culture University, Taipei, Taiwan.
authors.forename: Kuan-Hung
authors.initials: KH
authors.lastname: Lin
authors.affiliation: Department of International Business, Ming Chuan University, Taipei, Taiwan.
authors.forename: Chia-Hui
authors.initials: CH
authors.lastname: Yen
authors.affiliation: Department of Pediatrics, Taipei City Hospital Zhongxing Branch, Taipei, Taiwan.
authors.forename: Chien-Hung
authors.initials: CH
authors.lastname: Lin
mesh_terms: D016229:Amyloid beta-Peptides / Q000009:adverse effects / Q000037:antagonists & inhibitors; D002478:Cells, Cultured; D006801:Humans; D028361:Mitochondrial Diseases / Q000209:etiology* / Q000517:prevention & control*; D058953:Neural Stem Cells; D018696:Neuroprotective Agents; D018384:Oxidative Stress / Q000187:drug effects* / Q000235:genetics; D047495:PPAR gamma / Q000502:physiology*; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology*; D045162:Thiazolidinediones / Q000494:pharmacology*
chemical_list: D016229:Amyloid beta-Peptides; D018696:Neuroprotective Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone
keywords: Aβ; PGC1α; PPARγ; hNSCs