Curcumin Downregulates GSK3 and Cdk5 in Scopolamine-Induced Alzheimer's Disease Rats Abrogating Aβ40/42 and Tau Hyperphosphorylation
Curcumin Downregulates GSK3 and Cdk5 in Scopolamine-Induced Alzheimer's Disease Rats Abrogating Aβ40/42 and Tau Hyperphosphorylation
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DOI：
10.3233/adr-190135
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发表时间：
2019-01-01
影响因子：
3.2
通讯作者：
Hamid, Mas R. W. Abdul
中科院分区：
文献类型：
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作者：
Das, Tushar Kanti;Jana, Piyali;Hamid, Mas R. W. Abdul
阿尔茨海默病(AD)是痴呆症最常见的形式。细胞外淀粉样β蛋白(Aβ)聚集和tau蛋白过度磷酸化是AD的关键驱动因素。糖原合成酶激酶3(GSK3)和细胞周期蛋白依赖性激酶5(CDK5)被认为是仲裁tau异常过度磷酸化的主要指标。因此，我们在本研究中评价了姜黄素对东莨菪碱诱导的AD大鼠的疗效及其作用机制。我们发现，与未治疗的AD大鼠相比，姜黄素治疗的AD大鼠显著降低了脑和血浆中Aβ(40)和Aβ(42)的水平。此外，姜黄素治疗后AD大鼠血清Ser396(PHF13)、Ser202/Thr205(AT8)和Aβ(40/42)(MOAB2)的磷酸化tau水平显著降低。姜黄素可显著降低AD大鼠脑组织中GSK3的活性形式磷酸化GSK3β(Tyr216)和总GSK3β的含量。此外，在姜黄素治疗的AD大鼠，CDK5及其激活物p35和p25的表达显著降低。姜黄素治疗后AD大鼠CDK5、p35、p25和GSK3β表达降低，可能导致Aβ聚集减少和tau过度磷酸化，从而改善AD。姜黄素可部分逆转AD大鼠空间记忆和运动功能障碍。因此，姜黄素作为姜黄中的一种天然化合物，可能是一种更有效的治疗人类阿尔茨海默病的药物。
Alzheimer's disease (AD) is the most common form of dementia. Extracellular amyloid-beta (A beta) aggregation and tau hyperphosphorylation are the key drivers of AD. Glycogen synthase kinase 3 (GSK3) and cyclin dependent kinase 5 (Cdk5) have been known as leading applicants arbitrating abnormal tau hyperphosphorylation. Thus, we evaluated the efficacy and underlying mechanism of action of curcumin in scopolamine-induced AD rats in our study. We found that curcumin-treated AD rats markedly reduced the levels of A beta(40) and A beta(42) in the brain and in the plasma in comparison to untreated AD rats. Moreover, the levels of phosphorylated tau at Ser396 (PHF13), Ser202/Thr205 (AT8), and A beta(40/42) (MOAB2) were decreased significantly in AD rats treated with curcumin. Phospho-GSK3 beta (Tyr216), the active form of GSK3 beta, and total GSK3 beta were significantly decreased in AD rats treated with curcumin. Furthermore, Cdk5 and its activators p35 and p25 were significantly decreased in curcumin-treated AD rats. The reduced levels of Cdk5, p35, p25, and GSK3 beta in curcumin-treated AD rats may result decreased A beta aggregation and tau hyperphosphorylation, thus ameliorating AD. Impaired spatial memory and locomotor activity in AD rats were partially reversed by curcumin. Therefore, curcumin, as a natural compound present in turmeric, may be a more effective therapeutic agent in the treatment of AD in humans.