Tobacco Smoke Exposure Impairs Brain Insulin/IGF Signaling: Potential Co-Factor Role in Neurodegeneration
Tobacco Smoke Exposure Impairs Brain Insulin/IGF Signaling: Potential Co-Factor Role in Neurodegeneration
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DOI：
10.3233/jad-150664
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发表时间：
2016-01-01
影响因子：
4
通讯作者：
de la Montea, Suzanne M.
中科院分区：
文献类型：
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作者：
Deochand, Chetram;Tong, Ming;de la Montea, Suzanne M.
背景：人类研究表明，吸烟是认知障碍和神经退行性疾病（包括阿尔茨海默病（AD））的危险因素。然而，实验数据连接烟草烟雾暴露的神经退行性疾病的潜在介质，包括在脑胰岛素和胰岛素样生长因子（IGF）信号的损害在AD是lacked.Objective：本研究测试的假设，香烟烟雾（CS）暴露可以损害脑胰岛素/IGF信号和改变AD相关蛋白的表达。成年雄性A/J小鼠暴露于空气8周（A8）、CS 4或8周（CS4、CS 8）或CS 8后恢复2周（CS 8 +R）。结果：CS暴露对胰岛素/IGF和胰岛素受体底物（IRS）蛋白和磷酸化蛋白的影响与mRNA相比显著。CS4或CS 8暴露的主要后果是显著降低胰岛素R、IGF-1 R、IRS-1和酪氨酸磷酸化胰岛素R和IGF-1 R蛋白。巧合的是，这些效应在CS 8 +R组中甚至更大。此外，在CS4、CS 8和CS 8 +R组中，抑制下游信号传导的S312-IRS-1的相对水平增加。相应地，CS和CS 8 +R暴露抑制了通过Akt、PRAS 40和/或p70 S6 K进行信号传导所需的蛋白质和磷蛋白的表达，增加了A β PP-A β，并减少了ASPH蛋白，其是胰岛素/IGF-1信号传导的靶点。二手CS暴露导致大脑中的分子和生化异常，与AD中的发现重叠，尽管短期停用CS，但许多这些效应仍持续或恶化。
Background: Human studies suggest tobacco smoking is a risk factor for cognitive impairment and neurodegeneration, including Alzheimer's disease (AD). However, experimental data linking tobacco smoke exposures to underlying mediators of neurodegeneration, including impairments in brain insulin and insulin-like growth factor (IGF) signaling in AD are lacking.Objective: This study tests the hypothesis that cigarette smoke (CS) exposures can impair brain insulin/IGF signaling and alter expression of AD-associated proteins.Methods: Adult male A/J mice were exposed to air for 8 weeks (A8), CS for 4 or 8 weeks (CS4, CS8), or CS8 followed by 2 weeks recovery (CS8+R). Gene expression was measured by qRT-PCR analysis and proteins were measured by multiplex bead-based or direct binding duplex ELISAs.Results: CS exposure effects on insulin/IGF and insulin receptor substrate (IRS) proteins and phosphorylated proteins were striking compared with the mRNA. The main consequences of CS4 or CS8 exposures were to significantly reduce insulin R, IGF-1R, IRS-1, and tyrosine phosphorylated insulin R and IGF-1R proteins. Paradoxically, these effects were even greater in the CS8+R group. In addition, relative levels of S312-IRS-1, which inhibits downstream signaling, were increased in the CS4, CS8, and CS8+R groups. Correspondingly, CS and CS8+R exposures inhibited expression of proteins and phosphoproteins required for signaling through Akt, PRAS40, and/or p70S6K, increased A beta PP-A beta, and reduced ASPH protein, which is a target of insulin/IGF-1 signaling.Conclusion: Secondhand CS exposures caused molecular and biochemical abnormalities in brain that overlap with the findings in AD, and many of these effects were sustained or worsened despite short-term CS withdrawal.