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

Rosiglitazone activation of PPARγ-dependent pathways is neuroprotective in human neural stem... 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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Neurobiology of Aging Elsevier

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

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Publisher
Elsevier
Copyright
Copyright © 2016 Elsevier Inc.
ISSN
0197-4580
D.O.I.
10.1016/j.neurobiolaging.2016.01.132
Publisher site
See Article on Publisher Site

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.

Journal

Neurobiology of AgingElsevier

Published: Apr 1, 2016

References

  • Tau accumulation activates the unfolded protein response by impairing endoplasmic reticulum-associated degradation
    Abisambra, J.F.; Jinwal, U.K.; Blair, L.J.; O'Leary, J.C.; Li, Q.; Brady, S.; Wang, L.; Guidi, C.E.; Zhang, B.; Nordhues, B.A.; Cockman, M.; Suntharalingham, A.; Li, P.; Jin, Y.; Atkins, C.A.; Dickey, C.A.
  • The role of anti-inflammatory drugs in the prevention and treatment of Alzheimer's disease
    Breitner, J.C.
  • PPARgamma rescue of the mitochondrial dysfunction in Huntington's disease
    Chiang, M.C.; Chern, Y.; Huang, R.N.
  • The dysfunction of hepatic transcriptional factors in mice with Huntington's disease
    Chiang, M.C.; Chern, Y.; Juo, C.G.
  • Beta-adrenoceptor pathway enhances mitochondrial function in human neural stem cells via rotary cell culture system
    Chiang, M.C.; Lin, H.; Cheng, Y.C.; Yen, C.H.; Huang, R.N.; Lin, K.H.
  • The neuroprotective role of metformin in advanced glycation end product treated human neural stem cells is AMPK-dependent
    Chung, M.M.; Chen, Y.L.; Pei, D.; Cheng, Y.C.; Sun, B.; Nicol, C.J.; Yen, C.H.; Chen, H.M.; Liang, Y.J.; Chiang, M.C.
  • Methylglyoxal impairs glucose metabolism and leads to energy depletion in neuronal cells–protection by carbonyl scavengers
    de Arriba, S.G.; Stuchbury, G.; Yarin, J.; Burnell, J.; Loske, C.; Munch, G.
  • Central activation of PPAR-gamma ameliorates diabetes induced cognitive dysfunction and improves BDNF expression
    Kariharan, T.; Nanayakkara, G.; Parameshwaran, K.; Bagasrawala, I.; Ahuja, M.; Abdel-Rahman, E.; Amin, A.T.; Dhanasekaran, M.; Suppiramaniam, V.; Amin, R.H.
  • Pan-PPAR modulation effectively protects APP/PS1 mice from amyloid deposition and cognitive deficits
    Kummer, M.P.; Schwarzenberger, R.; Sayah-Jeanne, S.; Dubernet, M.; Walczak, R.; Hum, D.W.; Schwartz, S.; Axt, D.; Heneka, M.T.
  • Insulin resistance contributes to aberrant stress responses in the Tg2576 mouse model of Alzheimer's disease
    Pedersen, W.A.; Flynn, E.R.
  • Rosiglitazone attenuates learning and memory deficits in Tg2576 Alzheimer mice
    Pedersen, W.A.; McMillan, P.J.; Kulstad, J.J.; Leverenz, J.B.; Craft, S.; Haynatzki, G.R.
  • Amyloid beta, mitochondrial structural and functional dynamics in Alzheimer's disease
    Reddy, P.H.
  • Alzheimer's disease: genes, proteins, and therapy
    Selkoe, D.J.
  • Rosiglitazone enhances learning, place cell activity, and synaptic plasticity in middle-aged rats
    Wang, B.W.; Hok, V.; Della-Chiesa, A.; Callaghan, C.; Barlow, S.; Tsanov, M.; Bechara, R.; Irving, E.; Virley, D.J.; Upton, N.; O'Mara, S.M.
  • Rosiglitazone prevents the memory deficits induced by amyloid-beta oligomers via inhibition of inflammatory responses
    Xu, S.; Guan, Q.; Wang, C.; Wei, X.; Chen, X.; Zheng, B.; An, P.; Zhang, J.; Chang, L.; Zhou, W.; Mody, I.; Wang, Q.
  • Causes of oxidative stress in Alzheimer disease
    Zhu, X.; Su, B.; Wang, X.; Smith, M.A.; Perry, G.

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