Increased tau phosphorylation and impaired brain insulin/IGF signaling in mice fed a high fat/high cholesterol diet.
Increased tau phosphorylation and impaired brain insulin/IGF signaling in mice fed a high fat/high cholesterol diet.
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DOI：
10.3233/jad-2012-121030
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发表时间：
2013
期刊：
影响因子：
--
通讯作者：
Thirumangalakudi L
中科院分区：
文献类型：
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作者：
Bhat NR;Thirumangalakudi L
先前的研究表明，高脂肪/高胆固醇饮食导致小鼠工作记忆丧失，与神经炎性变化和AβPP处理增加有关(Thirumangalakudi等人)。J·神经化学。106：475-485；2008)。为了进一步探索认知障碍分子相关性的本质，在这项研究中，我们检测了tau磷酸化、胰岛素/IGF-1信号(包括GSK3)和特定突触蛋白水平的变化。用抗磷酸化tau抗体(即PHF1和磷酸化-Thr-231tau)饲喂HFC 2个月的C57BL/6小鼠海马区的免疫印迹分析表明，存在过度磷酸化的tau。Tau的磷酸化与激活的GSK3有关，GSK3是一种重要的tau激酶，通常在胰岛素/IGF信号(IIS)的控制下保持不活跃。IIS本身由于高脂饮食而受损，胰岛素受体底物-1和磷酸化Akt水平下调证实了这一点。免疫印迹分析显示，HFC刺激后突触前蛋白(即突触素)水平没有明显变化，突触后蛋白PSD95和树突棘特异性蛋白DREBRIN明显下调，表明突触可塑性改变。这一结果与之前同一模型的研究结果一致，表明高饮食脂肪/胆固醇会引起大脑胰岛素抵抗，并改变IIS，导致“正常”小鼠出现类似阿尔茨海默病(AD)的认知障碍。
Previous studies demonstrated that a high fat/high cholesterol (HFC) diet results in a loss of working memory in mice correlated with neuroinflammatory changes and increased AβPP processing (Thirumangalakudi et al. J. Neurochem. 106:475–485; 2008). To further explore the nature of the molecular correlates of cognitive impairment, in this study, we examined changes in tau phosphorylation, insulin/IGF-1 signaling including GSK3 and levels of specific synaptic proteins. Immunoblot analysis of hippocampal tissue from C57BL/6 mice fed HFC for 2 months with anti-phospho-tau (i.e., PHF1 and phospho-Thr-231 tau) antibodies demonstrated the presence of hyperphosphorylated tau. The tau phosphorylation correlated with activated GSK3, a prominent tau kinase normally kept inactive under the control of insulin/IGF signaling (IIS). That IIS itself was impaired due to the hyperlipidemic diet was confirmed by a down-regulation of insulin receptor substrate-1 and phospho-Akt and levels. Although no significant changes in the levels of the pre-synaptic protein i.e., synaptophysin in response to HFC were apparent in immunoblot analysis, there was a clear down-regulation of the post-synaptic protein, PSD95 and drebrin, a dendritic spine-specific protein, indicative of altered synaptic plasticity. The results, in concert with previous findings with the same model, suggest that high dietary fat/cholesterol elicits brain insulin resistance and altered IIS leading to Alzheimer’s disease (AD)-like cognitive impairment in ‘normal’ mice.