Regulation of the phosphatase calcineurin by insulin-like growth factor I unveils a key role of astrocytes in Alzheimer's pathology
Regulation of the phosphatase calcineurin by insulin-like growth factor I unveils a key role of astrocytes in Alzheimer's pathology
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DOI：
10.1038/mp.2011.128
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发表时间：
2012-07-01
影响因子：
11
通讯作者：
Torres-Aleman, I.
中科院分区：
文献类型：
--
作者：
Fernandez, A. M.;Jimenez, S.;Torres-Aleman, I.
胰岛素样生长因子I(IGF-I)信号在阿尔茨海默病(AD)中是有益的还是有害的仍然存在争议。我们现在表明，IGF-I竞争性调节反应性而不是静止的星形胶质细胞中的磷酸酶钙调神经磷酸酶，从而推动阿尔茨海默病的病理。钙调神经磷酸酶使转录因子Foxo3去磷酸化，以响应肿瘤坏死因子-α(肿瘤坏死因子-α)，这是一种在AD中增加的炎性细胞因子，激活星形胶质细胞中的核因子-kappa B(NF-kappa B)炎症信号。反过来，在肿瘤坏死因子α刺激的星形胶质细胞中，IGF-I通过重新招募转录因子过氧化物酶体增殖物激活受体-伽马来灭活并取代钙调神经磷酸酶中的Foxo3，并抑制NF-kappa B信号转导。这种拮抗机制可逆地推动了AD小鼠的疾病进程，即使在晚期也是如此。由于这种钙调神经磷酸酶/Foxo3/核因子kappa B通路的特征存在于人的AD脑中，IGF-I可能通过拮抗它而有益于治疗。《分子精神病学》(2012年)17705-718；DOI：10.1038/mp.2011.128；2011年10月18日在线发布
Whether insulin-like growth factor I (IGF-I) signaling in Alzheimer's disease (AD) is beneficial or detrimental remains controversial. We now show that a competitive regulation by IGF-I of the phosphatase calcineurin in reactive, but not in quiescent astrocytes drives Alzheimer's pathology. Calcineurin de-phosphorylates the transcription factor Foxo3 in response to tumor necrosis factor-alpha (TNF alpha), an inflammatory cytokine increased in AD, activating nuclear factor-kappa B (NF kappa B) inflammatory signaling in astrocytes. In turn, IGF-I inactivates and displaces Foxo3 from calcineurin in TNF alpha-stimulated astrocytes by recruiting the transcription factor peroxisome proliferator-activated receptor-gamma, and NF kappa B signaling is inhibited. This antagonistic mechanism reversibly drives the course of the disease in AD mice, even at advanced stages. As hallmarks of this calcineurin/Foxo3/NF kappa B pathway are present in human AD brains, treatment with IGF-I may be beneficial by antagonizing it. Molecular Psychiatry (2012) 17, 705-718; doi:10.1038/mp.2011.128; published online 18 October 2011