Curcumin Ameliorates Neuroinflammation, Neurodegeneration, and Memory Deficits in p25 Transgenic Mouse Model that Bears Hallmarks of Alzheimer's Disease.
Curcumin Ameliorates Neuroinflammation, Neurodegeneration, and Memory Deficits in p25 Transgenic Mouse Model that Bears Hallmarks of Alzheimer's Disease.
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DOI：
10.3233/jad-170093
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发表时间：
2017
期刊：
影响因子：
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通讯作者：
Kesavapany S
中科院分区：
文献类型：
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作者：
Sundaram JR;Poore CP;Sulaimee NHB;Pareek T;Cheong WF;Wenk MR;Pant HC;Frautschy SA;Low CM;Kesavapany S
多项研究表明，神经炎症确实与神经退行性疾病的病理相关。然而，近期抗炎药物在神经退行性疾病临床试验中的失败强调了需要更好地理解神经炎症过程的复杂性，以揭示其与神经退行性变的联系。细胞周期蛋白依赖性激酶5（Cdk5）因产生其过度激活因子p25而活性失调，这参与了类似阿尔茨海默病（AD）的tau蛋白和淀粉样蛋白病理的形成。近期研究表明p25/Cdk5过度激活与强烈的神经炎症之间存在关联。此外，我们最近利用一种过表达p25的转基因小鼠（p25Tg）报道了p25/Cdk5过度激活诱导的炎症反应与神经退行性变化之间的新联系。在本研究中，我们旨在了解早期使用一种有效的天然抗炎剂姜黄素对p25介导的神经炎症以及p25Tg小鼠神经退行性变进展的影响。本研究结果表明，姜黄素有效地对抗了p25Tg小鼠中p25介导的神经胶质激活以及促炎趋化因子/细胞因子的产生。此外，这种姜黄素介导的对神经炎症的抑制减少了p25诱导的tau/淀粉样蛋白病理的进展，进而改善了p25诱导的认知障碍。人们普遍认为，要治疗AD，必须针对病理变化的早期阶段，以保护神经元免受不可逆损伤。与此相符，我们的结果表明，早期干预炎症可以减少类似AD的病理结果的进展。此外，我们的数据为姜黄素类物质在治疗与炎症相关的神经退行性疾病中的潜在应用提供了理论依据。
Several studies have indicated that neuroinflammation is indeed associated with neurodegenerative disease pathology. However, failures of recent clinical trials of anti-inflammatory agents in neurodegenerative disorders have emphasized the need to better understand the complexity of the neuroinflammatory process in order to unravel its link with neurodegeneration. Deregulation of Cyclin-dependent kinase 5 (Cdk5) activity by production of its hyperactivator p25 is involved in the formation of tau and amyloid pathology reminiscent of Alzheimer’s disease (AD). Recent studies show an association between p25/Cdk5 hyperactivation and robust neuroinflammation. In addition, we recently reported the novel link between the p25/Cdk5 hyperactivation-induced inflammatory responses and neurodegenerative changes using a transgenic mouse that overexpresses p25 (p25Tg). In this study, we aimed to understand the effects of early intervention with a potent natural anti-inflammatory agent, curcumin, on p25-mediated neuroinflammation and the progression of neurodegeneration in p25Tg mice. The results from this study showed that curcumin effectively counteracted the p25-mediated glial activation and pro-inflammatory chemokines/cytokines production in p25Tg mice. Moreover, this curcumin-mediated suppression of neuroinflammation reduced the progression of p25-induced tau/amyloid pathology and in turn ameliorated the p25-induced cognitive impairments. It is widely acknowledged that to treat AD, one must target the early-stage of pathological changes to protect neurons from irreversible damage. In line with this, our results demonstrated that early intervention of inflammation could reduce the progression of AD-like pathological outcomes. Moreover, our data provide a rationale for the potential use of curcuminoids in the treatment of inflammation associated neurodegenerative diseases.