Peroxisome proliferator-activated receptor gamma up-regulates the Bcl-2 anti-apoptotic protein in neurons and induces mitochondrial stabilization and protection against oxidative stress and apoptosis

Fuenzalida K.; Quintanilla R.; Ramos, P; Piderit, D; Fuentealba, RA; Martinez, G; Inestrosa, NC; Bronfman, M

Abstract

Peroxisome proliferator-activated receptor γ (PPARγ) has been proposed as a therapeutic target for neurodegenerative diseases because of its anti-inflammatory action in glial cells. However, PPARγ agonists prevent β-amyloid (Aβ)-induced neurodegeneration in hippocampal neurons, and PPARγ is activated by the nerve growth factor (NGF) survival pathway, suggesting a neuroprotective anti-inflammatory independent action. Here we show that the PPARγ 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 PPARγ 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 H 2O 2. Conversely, cells expressing a dominant negative mutant of PPARγ 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 PPARγ present a 4-to 5-fold increase in Bcl-2 protein content, whereas in dominant negative PPARγ-expressing cells, Bcl-2 is barely detected. Bcl-2 knockdown by small interfering RNA in cells overexpressing PPARγ results in increased sensitivity to Aβ and oxidative stress, further suggesting that Bcl-2 up-regulation mediates PPARγ protective effects. PPARγ prosurvival action is independent of the signal-regulated MAPK or the Akt prosurvival pathways. Altogether, these data suggest that PPARγ supports survival in neurons in part through a mechanism involving increased expression of Bcl-2. © 2007 by The American Society for Biochemistry and Molecular Biology, Inc.

Más información

Título según WOS: Peroxisome proliferator-activated receptor gamma up-regulates the Bcl-2 anti-apoptotic protein in neurons and induces mitochondrial stabilization and protection against oxidative stress and apoptosis
Título según SCOPUS: 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
Título de la Revista: JOURNAL OF BIOLOGICAL CHEMISTRY
Volumen: 282
Número: 51
Editorial: AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Fecha de publicación: 2007
Página de inicio: 37006
Página final: 37015
Idioma: English
URL: http://www.jbc.org/cgi/doi/10.1074/jbc.M700447200
DOI:

10.1074/jbc.M700447200

Notas: ISI, SCOPUS