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

Loading next page...
 
/lp/elsevier/rosiglitazone-activation-of-ppar-dependent-pathways-is-neuroprotective-CwgOhgl7Tx
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.

You’re reading a free preview. Subscribe to read the entire article.


DeepDyve is your
personal research library

It’s your single place to instantly
discover and read the research
that matters to you.

Enjoy affordable access to
over 12 million articles from more than
10,000 peer-reviewed journals.

All for just $49/month

Explore the DeepDyve Library

Unlimited reading

Read as many articles as you need. Full articles with original layout, charts and figures. Read online, from anywhere.

Stay up to date

Keep up with your field with Personalized Recommendations and Follow Journals to get automatic updates.

Organize your research

It’s easy to organize your research with our built-in tools.

Your journals are on DeepDyve

Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.

All the latest content is available, no embargo periods.

See the journals in your area

Monthly Plan

  • Read unlimited articles
  • Personalized recommendations
  • No expiration
  • Print 20 pages per month
  • 20% off on PDF purchases
  • Organize your research
  • Get updates on your journals and topic searches

$49/month

Start Free Trial

14-day Free Trial

Best Deal — 39% off

Annual Plan

  • All the features of the Professional Plan, but for 39% off!
  • Billed annually
  • No expiration
  • For the normal price of 10 articles elsewhere, you get one full year of unlimited access to articles.

$588

$360/year

billed annually
Start Free Trial

14-day Free Trial