Topical ocular administration of the GLP-1 receptor agonist liraglutide arrests hyperphosphorylated tau-triggered diabetic retinal neurodegeneration via activation of GLP-1R/Akt/GSK3β signaling
Topical ocular administration of the GLP-1 receptor agonist liraglutide arrests hyperphosphorylated tau-triggered diabetic retinal neurodegeneration via activation of GLP-1R/Akt/GSK3β signaling
复制标题
GLP-1 受体激动剂利拉鲁肽局部眼部给药通过激活 GLP-1R/Akt/GSK3β 信号传导阻止过度磷酸化 tau 触发的糖尿病视网膜神经变性
DOI：
10.1016/j.neuropharm.2019.04.018
复制
发表时间：
2019-07
期刊：
影响因子：
--
通讯作者：
Ying Ying
中科院分区：
文献类型：
--
作者：
Xing-sheng Shu;Yilin Zhang;Meiqi Li;Xiaoyan Huang;Yangfan Yang;Junhui Zeng;Yingying Zhao;Xiaomei Wang;Weizhen Zhang;Ying Ying
糖尿病视网膜神经变性，特别是视网膜神经节细胞（RGCs）凋亡之前发生的视网膜神经节细胞（RGCs）的突触神经变性，可能代表糖尿病视网膜病变（DR）发病机制中的最早事件。我们先前的研究确定了过度磷酸化tau蛋白是糖尿病RGCs突触神经变性的关键毒性介质。因此，靶向tau蛋白的治疗药物可能是阻止DR进展的一种有前景的策略。胰高血糖素样肽1受体（GLP-1 R）激动剂（包括利拉鲁肽）可以通过降低脑中tau蛋白的过度磷酸化来改善阿尔茨海默病和糖尿病模型中的神经退行性特征。还发现利拉鲁肽可预防糖尿病小鼠的视网膜神经细胞凋亡/丧失。然而，利拉鲁肽是否可以预防RGC的糖尿病突触变性，以及其神经保护作用（如果有的话）是由于减轻视网膜tau蛋白过度磷酸化仍然未知。在此，使用充分表征的高脂饮食（HFD）诱导的糖尿病小鼠模型，我们表明利拉鲁肽局部眼部给药逆转了HFD诱导的糖尿病中过度磷酸化tau触发的RGCs突触变性。当GLP-1 R或Akt分别与GLP-1 R拮抗剂exendin-（9-39）或Akt抑制剂MK 2206局部联合给药抑制时，利拉鲁肽对糖尿病视网膜的神经保护作用消失。然而，通过玻璃体内注射si-GSK 3 β敲低GSK 3 β可恢复利拉鲁肽因Akt失活而消除的神经保护作用。因此，我们目前的研究表明，利拉鲁肽可以通过激活GLP-1 R/Akt/GSK 3 β信号传导来阻止过度磷酸化tau蛋白触发的视网膜神经变性。我们的研究结果还表明，局部眼部应用利拉鲁肽可被视为在DR早期发作时治疗视网膜tau蛋白病变的潜在有用策略。
Diabetic retinal neurodegeneration, in particular synaptic neurodegeneration of retinal ganglion cells (RGCs) occurring before RGCs apoptosis, may represent the earliest event in the pathogenesis of diabetic retinopathy (DR). Our previous study identified hyperphosphorylated-tau as a critical toxic mediator in diabetic RGCs synaptic neurodegeneration. Thus, therapeutic agents targeting to tau may appear as a promising strategy to arrest the progression of DR. The glucagon-like-peptide 1 receptor (GLP-1R) agonists, including liraglutide, can ameliorate neurodegenerative features in models of Alzheimer's disease and diabetes by decreasing tau hyperphosphorylation in the brain. Liraglutide has also been found to prevent retinal neural apoptosis/loss in diabetic mice. However, whether liraglutide can prevent diabetic synapse degeneration of RGCs, and its neuroprotective role, if any, is due to alleviating retinal tau hyperphosphorylation remain unknown. Here, using a well characterized high-fat diet (HFD)-induced diabetes mouse model, we showed that topical ocular administration of liraglutide reversed hyperphosphorylated tau-triggered RGCs synaptic degeneration in HFD-induced diabetes. The neuroprotective effect of liraglutide on diabetic retinae was abolished when GLP-1R or Akt was inhibited by topically co-administration with a GLP-1R antagonist, exendin-(9–39), or an Akt inhibitor MK2206, respectively. However, knock-down of GSK3β by intravitreal injection of si-GSK3β restored the neuroprotective effects of liraglutide abrogated by Akt inactivation. Thus, our present study demonstrated that liraglutide can arrest hyperphosphorylated tau-triggered retinal neurodegeneration via activation of GLP-1R/Akt/GSK3β signaling. Our results also propose that topical ocular application of liraglutide can be envisaged as a potentially useful strategy for the treatment of retinal tauopathy at the early onset of DR.
登录
查看更多内容
DOI：
10.1523/jneurosci.5927-11.2012
发表时间：
2012-02
期刊：
The Journal of Neuroscience
影响因子：
--
作者：
Kourosh Shahpasand;I. Uemura;Taro Saito;T. Asano;K. Hata;Keitaro Shibata;Y. Toyoshima;M. Hasegawa;S. Hisanaga
通讯作者：
Kourosh Shahpasand;I. Uemura;Taro Saito;T. Asano;K. Hata;Keitaro Shibata;Y. Toyoshima;M. Hasegawa;S. Hisanaga
影响因子：
81.5
作者：
T. Wong;C. Cheung;M. Larsen;Sanjay Sharma;R. Simó
通讯作者：
T. Wong;C. Cheung;M. Larsen;Sanjay Sharma;R. Simó
影响因子：
15.1
作者：
Lasagna-Reeves CA;Castillo-Carranza DL;Sengupta U;Clos AL;Jackson GR;Kayed R
通讯作者：
Kayed R
影响因子：
4.4
作者：
Chang, Richard Cheng-An;Shi, Liheng;Ko, Gladys Y. -P.
通讯作者：
Ko, Gladys Y. -P.
影响因子：
12.7
作者：
Li, Bin;Chohan, Muhammad Omar;Iqbal, Khalid
通讯作者：
Iqbal, Khalid