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.
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.
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发表时间：
2007
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通讯作者：
K. Fuenzalida;R. Quintanilla;P. Ramos;Daniela Piderit;Rodrigo A Fuentealba;G. Martínez;N. Inestrosa;M. Bronfman
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作者：
K. Fuenzalida;R. Quintanilla;P. Ramos;Daniela Piderit;Rodrigo A Fuentealba;G. Martínez;N. Inestrosa;M. Bronfman
过氧化物酶体增殖体激活受体（PPARgamma）因其在神经胶质细胞中的抗炎作用而被认为是神经退行性疾病的治疗靶点。然而，PPARgamma激动剂可预防β -淀粉样蛋白（Abeta）诱导的海马神经元神经退行性变，并且PPARgamma可通过神经生长因子（NGF）存活途径激活，提示其具有神经保护作用。本研究表明，PPARgamma激动剂罗格列酮（RGZ）分别保护海马和背根神经节神经元免受abeta诱导的线粒体损伤和NGF剥夺诱导的凋亡，并促进PC12细胞存活。在神经元和PC12细胞中，RGZ的保护作用与Bcl-2抗凋亡蛋白的表达增加有关。ngf分化的PC12神经元细胞组成性地过表达PPARgamma，可抵抗abbeta诱导的凋亡和形态学变化，并且在高达50微米H2O2的刺激下，线粒体功能完整，活性氧没有增加。相反，表达PPARgamma显性负突变体的细胞表现出abeta诱导的凋亡增加和神经元样形态的破坏，并且对氧化应激诱导的线粒体功能损伤高度敏感。过表达PPARgamma的细胞Bcl-2蛋白含量增加4- 5倍，而在显性PPARgamma阴性表达细胞中，几乎检测不到Bcl-2。在过表达PPARgamma的细胞中，小干扰RNA敲低Bcl-2导致对β和氧化应激的敏感性增加，进一步表明Bcl-2上调介导了PPARgamma的保护作用。PPARgamma促进生存的作用独立于信号调节的MAPK或Akt促进生存的途径。综上所述，这些数据表明PPARgamma在一定程度上通过增加Bcl-2表达的机制支持神经元存活。
Peroxisome proliferator-activated receptor gamma (PPARgamma) has been proposed as a therapeutic target for neurodegenerative diseases because of its anti-inflammatory action in glial cells. However, PPARgamma agonists preventbeta-amyloid (Abeta)-induced neurodegeneration in hippocampal neurons, and PPARgamma is activated by the nerve growth factor (NGF) survival pathway, suggesting a neuroprotective anti-inflammatory independent action. Here we show that the PPARgamma agonist rosiglitazone (RGZ) protects hippocampal and dorsal root ganglion neurons against Abeta-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 PPARgamma are resistant to Abeta-induced apoptosis and morphological changes and show functionally intact mitochondria and no increase in reactive oxygen species when challenged with up to 50 microM H2O2. Conversely, cells expressing a dominant negative mutant of PPARgamma show increased Abeta-induced apoptosis and disruption of neuronal-like morphology and are highly sensitive to oxidative stress-induced impairment of mitochondrial function. Cells overexpressing PPARgamma present a 4- to 5-fold increase in Bcl-2 protein content, whereas in dominant negative PPARgamma-expressing cells, Bcl-2 is barely detected. Bcl-2 knockdown by small interfering RNA in cells overexpressing PPARgamma results in increased sensitivity to Abeta and oxidative stress, further suggesting that Bcl-2 up-regulation mediates PPARgamma protective effects. PPARgamma prosurvival action is independent of the signal-regulated MAPK or the Akt prosurvival pathways. Altogether, these data suggest that PPARgamma supports survival in neurons in part through a mechanism involving increased expression of Bcl-2.