Rosiglitazone rescues human neural stem cells from amyloid-beta induced ER stress via PPAR�^ dependent signaling
Journal
Experimental Cell Research
Journal Volume
370
Journal Issue
2
Pages
312-321
Date Issued
2018
Author(s)
Abstract
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. ? 2018 Elsevier Inc.
SDGs
Other Subjects
2 chloro 5 nitrobenzanilide; actin; amyloid beta protein[1-42]; apoptosis signal regulating kinase 1; calcium; caspase 4; cytochrome c; cytochrome c oxidase; glucose regulated protein 78; glyceraldehyde 3 phosphate dehydrogenase; growth arrest and DNA damage inducible protein 153; peroxisome proliferator activated receptor gamma; rosiglitazone; voltage dependent anion channel; amyloid beta protein; neuroprotective agent; peroxisome proliferator activated receptor gamma; rosiglitazone; apoptosis; Article; calcium cell level; calcium homeostasis; cell viability; controlled study; disorders of mitochondrial functions; drug efficacy; drug mechanism; endoplasmic reticulum stress; enzyme activation; enzyme activity; evidence based practice; exploratory research; human; human cell; mitochondrial membrane potential; mitochondrial respiration; neural stem cell; neuroprotection; neurotoxicity; priority journal; protein phosphorylation; signal transduction; cell survival; drug effect; endoplasmic reticulum stress; metabolism; mitochondrion; nerve cell; neural stem cell; non insulin dependent diabetes mellitus; Amyloid beta-Peptides; Cell Survival; Diabetes Mellitus, Type 2; Endoplasmic Reticulum Stress; Humans; Membrane Potential, Mitochondrial; Mitochondria; Neural Stem Cells; Neurons; Neuroprotective Agents; PPAR gamma; Rosiglitazone
Type
journal article