Troglitazone, a thiazolidinedione, decreases tau phosphorylation through the inhibition of cyclin-dependent kinase 5 activity in SH-SY5Y neuroblastoma cells and primary neurons
Troglitazone, a thiazolidinedione, decreases tau phosphorylation through the inhibition of cyclin-dependent kinase 5 activity in SH-SY5Y neuroblastoma cells and primary neurons
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DOI：
10.1111/jnc.12264
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发表时间：
2013-09-01
影响因子：
4.7
通讯作者：
Han, Seol-Heui
中科院分区：
文献类型：
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作者：
Cho, Du-Hyong;Lee, Eun Joo;Han, Seol-Heui
过氧化物酶体增殖物激活受体γ(PPAR)激动剂噻唑烷二酮(TZDS)是用于治疗2型糖尿病的处方。此外，据报道，TZDS对阿尔茨海默病等神经退行性疾病有有益的影响。然而，这种效应背后的分子机制尚不完全清楚。在这里，我们研究了TZD的母药曲格列酮是否以及如何抑制tau的磷酸化。曲格列酮以剂量和时间依赖的方式降低tau-Thr(231)的磷酸化和细胞周期蛋白依赖性激酶5(CDK5)的特异性激活物p35。曲格列酮还降低了CDK5的酶活性，p35的裂解形式p25的异位表达恢复了曲格列酮引起的tau-Thr(231)磷酸化的降低。用可逆蛋白酶体抑制剂MG-132或不可逆的26S蛋白酶体特异性抑制剂lactacystin处理，均可显著逆转曲格列酮的抑制作用。然而，不可逆的特异性PPAR拮抗剂GW9662不改变所观察到的抑制作用。当使用其他TZD药物，吡格列酮和罗格列酮时，也发现了类似的结果。用不同的抑制剂处理发现曲格列酮抑制tau-Thr(231)的磷酸化和p35的表达不是通过糖原合成酶激酶3、蛋白激酶A和蛋白磷酸酶2A信号通路来实现的。最后，我们还发现，曲格列酮同样的抑制作用也适用于原代皮质神经元。综上所述，我们证明了TZDS通过抑制CDK5的活性来抑制tau-Thr(231)的磷酸化，这种抑制是通过p35的蛋白酶体降解和PPAR非依赖的信号通路来实现的。
The peroxisome proliferator-activated receptor gamma (PPAR) agonists thiazolidinediones (TZDs) are prescribed for the treatment of type 2 diabetes mellitus. Furthermore, it has been reported that TZDs have a beneficial effect on neurodegenerative disorders, such as Alzheimer's disease. However, the molecular mechanisms underlying this effect are not fully understood. Here, we investigated whether and how troglitazone, a parent TZD drug, inhibits tau phosphorylation. Treatment with troglitazone decreased tau-Thr(231) phosphorylation and p35, the specific activator of cyclin-dependent kinase 5 (CDK5), in a dose- and time-dependent manner. Troglitazone also decreased CDK5 enzymatic activity, and ectopic expression of p25, the cleaved and more active form of p35, restored the troglitazone-induced decrease in tau-Thr(231) phosphorylation. Treatment with either MG-132, a reversible proteasome inhibitor, or lactacystin, a specific and irreversible 26S proteasome inhibitor, significantly reversed the observed inhibitory effects of troglitazone. However, GW9662, a specific and irreversible PPAR antagonist, did not alter the observed inhibitory effects. Similar results were also found when other TZD drugs, pioglitazone and rosiglitazone, were used. Treatment with various inhibitors revealed that troglitazone-induced inhibitions of tau-Thr(231) phosphorylation and p35 expression were not mediated by glycogen synthase kinase 3, protein kinase A, and protein phosphatase 2A signaling pathways. Finally, we also found that the same observed inhibitory effects of troglitazone hold true for the use of primary cortical neurons. Taken together, we demonstrated that TZDs repressed tau-Thr(231) phosphorylation via the inhibition of CDK5 activity, which was mediated by the proteasomal degradation of p35 and a PPAR-independent signaling pathway.