A Putative Mechanism of Age-Related Synaptic Dysfunction Based on the Impact of IGF-1 Receptor Signaling on Synaptic CaMKIIα Phosphorylation.
A Putative Mechanism of Age-Related Synaptic Dysfunction Based on the Impact of IGF-1 Receptor Signaling on Synaptic CaMKIIα Phosphorylation.
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DOI：
10.3389/fnana.2018.00035
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发表时间：
2018
影响因子：
2.9
通讯作者：
Lee CC
中科院分区：
文献类型：
--
作者：
Ogundele OM;Pardo J;Francis J;Goya RG;Lee CC
胰岛素样生长因子1受体(IGF-1R)信号调节与炎症、神经发育、衰老和突触功能相关的下游蛋白的活性和磷酸化。除了控制钙电流外，胰岛素样生长因子-1R信号还通过多条信号通路调节钙调素依赖的蛋白激酶2α(CaMKⅡα)和丝裂原活化的蛋白激酶(MAPK/ERK)的活性。这些蛋白(CaMKII、α和MAPK)调节钙离子运动和长时程增强(LTP)。由于IGF1R控制着钙离子、CaMKIIα和MAPK信号的突触活性，因此，IGF1R在衰老过程中改变这些蛋白的突触表达和磷酸化的可能机制有待于进一步研究。在这项研究中，我们评估了脑内胰岛素样生长因子-1R的年龄依赖性变化与CaMKIIα/MAPK磷酸化的关系。此外，我们还阐明了CaMKIIα/MAPK相互作用失调可能与神经递质处理和突触功能改变有关的可能机制。选用出生后第80天(P80)、365天和730天的雄性C57BL/6 VGAT-Venus小鼠，研究与认知功能相关的两个脑区：海马区和前额叶皮质(PFC)的增龄性神经变化。应用高通量共聚焦成像和定量免疫印迹技术检测IGF1、IGF1R、CaMKIIα、p-CaMKIIα、MAPK和p-MAPK在全脑裂解液、海马区和皮质中的分布和表达。此外，我们还比较了P80、P365和P730的蛋白质表达模式和区域变化。最终，我们通过对P80、P365和P730脑组织标本的神经p-CaMKIIα和p-MAPK/ERK以及IGF-1R表达的定量，确定了CaMKIIα和MAPK的相对磷酸化模式。除了突触功能的改变外，我们的结果还显示老年小鼠全脑、海马区和皮质中神经性IGF-1/IGF-1R的表达减少。这与老年脑中磷酸化的神经丝裂原活化蛋白激酶(p-MAPK)显著上调和脑内总CaMKIIα(即CaMKIIα和p-CaMKIIα)的减少有关。综上所述，我们发现脑老化与神经胰岛素样生长因子-1/胰岛素样生长因子-1R表达的变化有关，并可能与参与长时程增强调节的突触蛋白激酶(CaMKIIα和MAPK)的磷酸化变化有关。
Insulin-like growth factor 1 receptor (IGF-1R) signaling regulates the activity and phosphorylation of downstream kinases linked to inflammation, neurodevelopment, aging and synaptic function. In addition to the control of Ca2+ currents, IGF-1R signaling modulates the activity of calcium-calmodulin-dependent kinase 2 alpha (CaMKIIα) and mitogen activated protein kinase (MAPK/ErK) through multiple signaling pathways. These proteins (CaMKIIα and MAPK) regulate Ca2+ movement and long-term potentiation (LTP). Since IGF-1R controls the synaptic activity of Ca2+, CaMKIIα and MAPK signaling, the possible mechanism through which an age-dependent change in IGF-1R can alter the synaptic expression and phosphorylation of these proteins in aging needs to be investigated. In this study, we evaluated the relationship between an age-dependent change in brain IGF-1R and phosphorylation of CaMKIIα/MAPK. Furthermore, we elucidated possible mechanisms through which dysregulated CaMKIIα/MAPK interaction may be linked to a change in neurotransmitter processing and synaptic function. Male C57BL/6 VGAT-Venus mice at postnatal days 80 (P80), 365 and 730 were used to study age-related neural changes in two brain regions associated with cognitive function: hippocampus and prefrontal cortex (PFC). By means of high throughput confocal imaging and quantitative immunoblotting, we evaluated the distribution and expression of IGF-1, IGF-1R, CaMKIIα, p-CaMKIIα, MAPK and p-MAPK in whole brain lysate, hippocampus and cortex. Furthermore, we compared protein expression patterns and regional changes at P80, P365 and P730. Ultimately, we determined the relative phosphorylation pattern of CaMKIIα and MAPK through quantification of neural p-CaMKIIα and p-MAPK/ErK, and IGF-1R expression for P80, P365 and P730 brain samples. In addition to a change in synaptic function, our results show a decrease in neural IGF-1/IGF-1R expression in whole brain, hippocampus and cortex of aged mice. This was associated with a significant upregulation of phosphorylated neural MAPK (p-MAPK) and decrease in total brain CaMKIIα (i.e., CaMKIIα and p-CaMKIIα) in the aged brain. Taken together, we showed that brain aging is associated with a change in neural IGF-1/IGF-1R expression and may be linked to a change in phosphorylation of synaptic kinases (CaMKIIα and MAPK) that are involved in the modulation of LTP.
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影响因子：
25
作者：
Allen, Duane;Bond, Chris T.;Lujan, Rafael;Ballesteros-Merino, Carmen;Lin, Mike T.;Wang, Kang;Klett, Nathan;Watanabe, Masahiko;Shigemoto, Ryuichi;Stackman, Robert W., Jr.;Maylie, James;Adelman, John P.
通讯作者：
Adelman, John P.
影响因子：
16.2
作者：
Gazit N;Vertkin I;Shapira I;Helm M;Slomowitz E;Sheiba M;Mor Y;Rizzoli S;Slutsky I
通讯作者：
Slutsky I
影响因子：
4.3
作者：
Griffith T;Tsaneva-Atanasova K;Mellor JR
通讯作者：
Mellor JR
DOI：
10.1073/pnas.88.9.3633
发表时间：
1991-05-01
影响因子：
11.1
作者：
CARNEY, JM;STARKEREED, PE;FLOYD, RA
通讯作者：
FLOYD, RA
DOI：
10.1080/23262133.2016.1261653
发表时间：
2016-01-01
期刊：
Neurogenesis (Austin, Tex.)
影响因子：
--
作者：
Chou, Fu-Sheng;Wang, Pei-Shan
通讯作者：
Wang, Pei-Shan