Rosiglitazone activation of PPARγ-dependent pathways is neuroprotective in human neural stem cells against amyloid-beta-induced mitochondrial dysfunction and oxidative stress

Neurobiol Aging. 2016 Apr:40:181-190. doi: 10.1016/j.neurobiolaging.2016.01.132. Epub 2016 Feb 27.

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.

Keywords: Aβ; PGC1α; PPARγ; hNSCs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Peptides* / adverse effects
  • Amyloid beta-Peptides* / antagonists & inhibitors
  • Cells, Cultured
  • Humans
  • Mitochondrial Diseases / etiology*
  • Mitochondrial Diseases / prevention & control*
  • Neural Stem Cells*
  • Neuroprotective Agents*
  • Oxidative Stress / drug effects*
  • Oxidative Stress / genetics
  • PPAR gamma / physiology*
  • Rosiglitazone
  • Signal Transduction / drug effects*
  • Signal Transduction / physiology*
  • Thiazolidinediones / pharmacology*

Substances

  • Amyloid beta-Peptides
  • Neuroprotective Agents
  • PPAR gamma
  • Thiazolidinediones
  • Rosiglitazone