PPARgamma agonists rescue increased phosphorylation of FGF14 at S226 in the Tg2576 mouse model of Alzheimer's disease.
PPARgamma agonists rescue increased phosphorylation of FGF14 at S226 in the Tg2576 mouse model of Alzheimer's disease.
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DOI：
10.1016/j.expneurol.2017.05.005
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发表时间：
2017-09
影响因子：
5.3
通讯作者：
Laezza F
中科院分区：
文献类型：
--
作者：
Hsu WJ;Wildburger NC;Haidacher SJ;Nenov MN;Folorunso O;Singh AK;Chesson BC;Franklin WF;Cortez I;Sadygov RG;Dineley KT;Rudra JS;Taglialatela G;Lichti CF;Denner L;Laezza F
阿尔茨海默病（AD）患者和Aβ病理学动物模型中的认知障碍可通过核受体过氧化物酶体增殖物激活受体-γ（PPARγ）激动剂（如罗格列酮（RSG））治疗得到改善。以前，我们证明了在Tg 2576 AD动物模型中，RSG治疗挽救了认知缺陷并减少了齿状回（DG）中颗粒神经元的异常活动，齿状回是记忆形成的关键区域。我们使用了质谱，共聚焦成像，电生理学和分裂荧光素酶测定和体外磷酸化和免疫途径分析的组合。使用无偏的，定量的nano-LC-MS/MS筛选，我们寻找DG颗粒神经元的RSG依赖性拯救的潜在分子靶点。我们发现，S226磷酸化的成纤维细胞生长因子14（FGF 14），一个辅助蛋白的电压门控Na+（Nav）通道所需的神经元放电，减少在Tg 2576小鼠治疗与RSG。使用共聚焦显微镜，我们证实了Tg 2576条件减少了DG AIS处的PanNav通道，并且Tg 2576小鼠的RSG治疗逆转了PanNav通道的减少。从先前发表的数据集的分析确定了与未处理和野生型对照相比，RSG处理的T2576中动作电位动力学的相关变化。体外磷酸化和质谱证实，多功能激酶GSK-3β（与AD高度相关的胰岛素信号传导的下游靶标）在S226处磷酸化FGF 14。FGF 14：Nav1.6通道复合物的组装和FGF 14对Nav1.6介导的电流的功能调节受到磷酸沉默S226 A突变的损害。质谱和生物化学数据的生物信息学途径分析揭示了一个高度互连的网络，包括PPARγ、FGF 14、SCN 8A（Nav 1.6）以及激酶GSK-3 β、酪蛋白激酶2β和ERK 1/2。这些结果将FGF 14确定为控制Aβ诱导的DG中神经元活动功能障碍的潜在的PPARγ敏感性靶标，该功能障碍是早期AD中记忆丧失的基础。
Cognitive impairment in humans with Alzheimer's disease (AD) and in animal models of Aβ-pathology can be ameliorated by treatments with the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARγ) agonists, such as rosiglitazone (RSG). Previously, we demonstrated that in the Tg2576 animal model of AD, RSG treatment rescued cognitive deficits and reduced aberrant activity of granule neurons in the dentate gyrus (DG), an area critical for memory formation. We used a combination of mass spectrometry, confocal imaging, electrophysiology and split-luciferase assay and in vitro phosphorylation and Ingenuity Pathway Analysis. Using an unbiased, quantitative nano-LC-MS/MS screening, we searched for potential molecular targets of the RSG-dependent rescue of DG granule neurons. We found that S226 phosphorylation of fibroblast growth factor 14 (FGF14), an accessory protein of the voltage-gated Na+ (Nav) channels required for neuronal firing, was reduced in Tg2576 mice upon treatment with RSG. Using confocal microscopy, we confirmed that the Tg2576 condition decreased PanNav channels at the AIS of the DG, and that RSG treatment of Tg2576 mice reversed the reduction in PanNav channels. Analysis from previously published data sets identified correlative changes in action potential kinetics in RSG-treated T2576 compared to untreated and wildtype controls. In vitro phosphorylation and mass spectrometry confirmed that the multifunctional kinase GSK–3β, a downstream target of insulin signaling highly implicated in AD, phosphorylated FGF14 at S226. Assembly of the FGF14:Nav1.6 channel complex and functional regulation of Nav1.6-mediated currents by FGF14 was impaired by a phosphosilent S226A mutation. Bioinformatics pathway analysis of mass spectrometry and biochemistry data revealed a highly interconnected network encompassing PPARγ, FGF14, SCN8A (Nav 1.6), and the kinases GSK–3 β, casein kinase 2β, and ERK1/2. These results identify FGF14 as a potential PPARγ-sensitive target controlling Aβ-induced dysfunctions of neuronal activity in the DG underlying memory loss in early AD.
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影响因子：
4.8
作者：
Farghaian, Hovik;Chen, Yu;Cole, Adam R.
通讯作者：
Cole, Adam R.
DOI：
10.1083/jcb.200805169
发表时间：
2008-12-15
期刊：
The Journal of cell biology
影响因子：
--
作者：
Bréchet A;Fache MP;Brachet A;Ferracci G;Baude A;Irondelle M;Pereira S;Leterrier C;Dargent B
通讯作者：
Dargent B
影响因子：
4.1
作者：
Budni, Josiane;Lobato, Kelly R.;Rodrigues, Ana Lucia S.
通讯作者：
Rodrigues, Ana Lucia S.
影响因子：
4.4
作者：
Berendt, Frank J.;Park, Kang-Sik;Trimmer, James S.
通讯作者：
Trimmer, James S.
影响因子：
6.8
作者：
Alshammari TK;Alshammari MA;Nenov MN;Hoxha E;Cambiaghi M;Marcinno A;James TF;Singh P;Labate D;Li J;Meltzer HY;Sacchetti B;Tempia F;Laezza F
通讯作者：
Laezza F