Estrogen protects neuronal cells from amyloid beta-induced apoptosis via regulation of mitochondrial proteins and function.
Estrogen protects neuronal cells from amyloid beta-induced apoptosis via regulation of mitochondrial proteins and function.
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DOI：
10.1186/1471-2202-7-74
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发表时间：
2006-11-03
期刊：
影响因子：
2.4
通讯作者：
Brinton, Roberta Diaz
中科院分区：
文献类型：
--
作者：
Nilsen, Jon;Chen, Shuhua;Irwin, Ronald W.;Iwamoto, Sean;Brinton, Roberta Diaz
阿尔茨海默病的神经退行性变与细胞凋亡增加有关，并且与β淀粉样蛋白水平增加平行，后者可诱导神经元细胞凋亡。在海马神经元的神经毒性损伤之前雌激素暴露促进神经元防御和对神经变性损伤（包括淀粉样蛋白β）的存活。尽管淀粉样蛋白β神经毒性的所有潜在分子机制尚未确定，但线粒体功能障碍，包括钙稳态改变和Bcl-2表达，与神经退行性脆弱性有关。本研究探讨了17β-雌二醇（17β-estradiol）对淀粉样β蛋白（amyloid beta，A β）诱导的大鼠海马神经元凋亡的抑制作用及其机制。在β淀粉样蛋白暴露之前，雌二醇治疗显著减少了凋亡神经元的数量和相关的静息细胞内钙水平的升高。淀粉样蛋白β暴露引起关键抗凋亡蛋白Bcl-2的下调，并导致Bax（一种已知促进细胞死亡的蛋白质）的线粒体易位，以及随后细胞色素c的释放。E2预处理可抑制淀粉样蛋白β诱导的Bcl-2表达的降低、Bax向线粒体的移位以及随后细胞色素c的释放。进一步暗示线粒体作为雌二醇作用的靶点，体内雌二醇处理增强了全脑线粒体的呼吸功能。此外，雌二醇预处理保护分离的线粒体对钙诱导的呼吸功能丧失。因此，我们认为雌二醇预处理通过激活抗凋亡机制限制线粒体功能障碍来保护β淀粉样蛋白神经毒性。
Neurodegeneration in Alzheimer's disease is associated with increased apoptosis and parallels increased levels of amyloid beta, which can induce neuronal apoptosis. Estrogen exposure prior to neurotoxic insult of hippocampal neurons promotes neuronal defence and survival against neurodegenerative insults including amyloid beta. Although all underlying molecular mechanisms of amyloid beta neurotoxicity remain undetermined, mitochondrial dysfunction, including altered calcium homeostasis and Bcl-2 expression, are involved in neurodegenerative vulnerability. In this study, we investigated the mechanism of 17β-estradiol-induced prevention of amyloid beta-induced apoptosis of rat hippocampal neuronal cultures. Estradiol treatment prior to amyloid beta exposure significantly reduced the number of apoptotic neurons and the associated rise in resting intracellular calcium levels. Amyloid beta exposure provoked down regulation of a key antiapoptotic protein, Bcl-2, and resulted in mitochondrial translocation of Bax, a protein known to promote cell death, and subsequent release of cytochrome c. E2 pretreatment inhibited the amyloid beta-induced decrease in Bcl-2 expression, translocation of Bax to the mitochondria and subsequent release of cytochrome c. Further implicating the mitochondria as a target of estradiol action, in vivo estradiol treatment enhanced the respiratory function of whole brain mitochondria. In addition, estradiol pretreatment protected isolated mitochondria against calcium-induced loss of respiratory function. Therefore, we propose that estradiol pretreatment protects against amyloid beta neurotoxicity by limiting mitochondrial dysfunction via activation of antiapoptotic mechanisms.
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DOI：
10.1073/pnas.94.8.3668
发表时间：
1997-04-15
影响因子：
11.1
作者：
Hsu, YT;Wolter, KG;Youle, RJ
通讯作者：
Youle, RJ
DOI：
10.1124/jpet.112.192138
发表时间：
2012-09-01
影响因子：
3.5
作者：
Johri, Ashu;Beal, M. Flint
通讯作者：
Beal, M. Flint
DOI：
10.1111/j.1749-6632.1999.tb07815.x
发表时间：
1999-01-01
期刊：
OXIDATIVE/ENERGY METABOLISM IN NEURODEGENERATIVE DISORDERS
影响因子：
--
作者：
Murphy, AN
通讯作者：
Murphy, AN
DOI：
10.1152/ajpcell.1998.275.3.c832
发表时间：
1998-09-01
影响因子：
5.5
作者：
Ichimiya, M;Chang, SH;Amstad, PA
通讯作者：
Amstad, PA
DOI：
10.1073/pnas.93.18.9893
发表时间：
1996-09-03
影响因子：
11.1
作者：
Murphy, AN;Bredesen, DE;Fiskum, G
通讯作者：
Fiskum, G