Rosiglitazone rescues human neural stem cells from amyloid-beta induced ER stress via PPARγ dependent signaling

Journal Article · Sat Sep 15 04:00:00 EDT 2018 · Experimental Cell Research

DOI:https://doi.org/10.1016/J.YEXCR.2018.06.033· OSTI ID:23082648

Lin, Chien-Hung ^[1]; Nicol, Christopher J.B. ^[2]; Cheng, Yi-Chuan ^[3]; Chen, Shiang-Jiuun ^[4]; Yen, Chia-Hui ^[5]; Huang, Rong-Nan ^[6]; Chiang, Ming-Chang ^[7]

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1. Department of Pediatrics, Taipei City Hospital Zhongxing Branch, Taipei 103 (China)
2. Departments of Pathology & Molecular Medicine and Biomedical & Molecular Sciences, and Division of Cancer Biology & Genetics, Cancer Research Institute, Queen's University, Kingston, Ontario (Canada)
3. Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Tao Yuan 333 (China)
4. Department of Life Science and Institute of Ecology and Evolutionary Biology, College of Life Science, National Taiwan University, Taipei 106 (China)
5. Department of International Business, Ming Chuan University, Taipei 111 (China)
6. Department of Entomology and Research Center for Plant-Medicine, National Taiwan University, Taipei 106 (China)
7. Department of Life Science, College of Science and Engineering, Fu Jen Catholic University, New Taipei City 242 (China)

Highlights: • Rosiglitazone rescued the Aβ decreased hNSCs survivability. • Rosiglitazone normalized ER stress in the hNSCs with Aβ. • Rosiglitazone improved ER and mitochondrial homeostasis in the hNSCs with Aβ. Peroxisome proliferator-activated receptor gamma (PPARγ) belongs to a family of ligand-activated nuclear receptors known to regulate many crucial physiological and pathological conditions. Indeed, altered PPARγ transcriptional activity contributes to metabolic syndromes (obesity and hyperglycemia associated with type 2 diabetes mellitus), stroke and neurodegenerative diseases. Various studies suggest that PPARγ agonists influence neuronal deficits in Alzheimer's Disease (AD) patients and rodent models of AD. Expression of amyloid-beta (Aβ), a neuropathological marker associated with the pathogenesis of AD neuronal impairment, is inversely correlated with the activation of PPARγ-dependent neuroprotective responses. Nevertheless, molecular mechanisms by which the effects of PPARγ agonists in AD remain to be clarified. Here, we explore the PPARγ signaling pathways and networks that protect against Aβ-induced endoplasmic reticulum (ER) stress (e.g., caspase 4, Bip, CHOP, ASK1 and ER calcium), cell death (e.g., viability and cytochrome c) and mitochondrial deficiency (e.g., maximal respiratory function, COX activity, and mitochondrial membrane potential) events in the human neural stem cells (hNSCs) treated with Aβ. Co-treatment with GW9662 (an antagonist of PPARγ) effectively blocked these protective effects by rosiglitazone, providing strong evidence that PPARγ-dependent signaling rescues hNSCs from Aβ-mediated toxicity. Together, our data suggest activation of PPARγ pathway might be critical to protecting against AD-related ER stress, ER disequilibrium and mitochondrial deficiency. These findings also improve our understanding of the role of PPARγ in hNSCs, and may aid in the development and implementation of new therapeutic strategies for the treatment of AD.

• OSTI ID: 23082648
• Journal Information: Experimental Cell Research, Journal Name: Experimental Cell Research Journal Issue: 2 Vol. 370; ISSN 0014-4827; ISSN ECREAL
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
APOPTOSIS
CYTOCHROMES
DIABETES MELLITUS
ENDOPLASMIC RETICULUM
MITOCHONDRIA
NERVOUS SYSTEM DISEASES
RECEPTORS
RODENTS
STEM CELLS