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J. Biol. Chem., Vol. 282, Issue 51, 37006-37015, December 21, 2007

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Peroxisome Proliferator-activated Receptor Up-regulates the Bcl-2 Anti-apoptotic Protein in Neurons and Induces Mitochondrial Stabilization and Protection against Oxidative Stress and Apoptosis^*

From the Centro de Regulación Celular y Patologia Joaquín V. Luco and Millennium Institute for Fundamental and Applied Biology, Department of Cellular and Molecular Biology, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Alameda 340, Santiago 114-D, Chile

Peroxisome proliferator-activated receptor (PPAR) has been proposed as a therapeutic target for neurodegenerative diseases because of its anti-inflammatory action in glial cells. However, PPAR agonists preventβ-amyloid (Aβ)-induced neurodegeneration in hippocampal neurons, and PPAR is activated by the nerve growth factor (NGF) survival pathway, suggesting a neuroprotective anti-inflammatory independent action. Here we show that the PPAR agonist rosiglitazone (RGZ) protects hippocampal and dorsal root ganglion neurons against Aβ-induced mitochondrial damage and NGF deprivation-induced apoptosis, respectively, and promotes PC12 cell survival. In neurons and in PC12 cells RGZ protective effects are associated with increased expression of the Bcl-2 anti-apoptotic protein. NGF-differentiated PC12 neuronal cells constitutively overexpressing PPAR are resistant to Aβ-induced apoptosis and morphological changes and show functionally intact mitochondria and no increase in reactive oxygen species when challenged with up to 50 µM H₂O₂. Conversely, cells expressing a dominant negative mutant of PPAR show increased Aβ-induced apoptosis and disruption of neuronal-like morphology and are highly sensitive to oxidative stress-induced impairment of mitochondrial function. Cells overexpressing PPAR present a 4- to 5-fold increase in Bcl-2 protein content, whereas in dominant negative PPAR-expressing cells, Bcl-2 is barely detected. Bcl-2 knockdown by small interfering RNA in cells overexpressing PPAR results in increased sensitivity to Aβ and oxidative stress, further suggesting that Bcl-2 up-regulation mediates PPAR protective effects. PPAR prosurvival action is independent of the signal-regulated MAPK or the Akt prosurvival pathways. Altogether, these data suggest that PPAR supports survival in neurons in part through a mechanism involving increased expression of Bcl-2.

Received for publication, January 16, 2007 , and in revised form, October 9, 2007.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 562-686-2833; Fax: 562-635-2849; E-mail: mbronfman{at}bio.puc.cl.

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