Modulation of p25 and inflammatory pathways by fisetin maintains cognitive function in Alzheimer's disease transgenic mice.
Modulation of p25 and inflammatory pathways by fisetin maintains cognitive function in Alzheimer's disease transgenic mice.
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DOI：
10.1111/acel.12185
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发表时间：
2014-04
期刊：
影响因子：
7.8
通讯作者：
Maher P
中科院分区：
文献类型：
--
作者：
Currais A;Prior M;Dargusch R;Armando A;Ehren J;Schubert D;Quehenberger O;Maher P
阿尔茨海默病（AD）是最常见的痴呆症类型。它是美国十大死因中唯一尚未制定预防策略的之一。尽管 AD 传统上与 β 淀粉样斑块和 tau 蛋白缠结的沉积有关，但越来越清楚的是，它涉及多个细胞系统的破坏。因此，达到单一目标不太可能给 AD 患者带来显着的益处。另一种方法是识别具有与疾病相关的多种生物活性的分子。非瑟酮是一种口服活性小分子，可以作用于与 AD 相关的许多靶途径。我们在此表明，对 3 至 12 个月大的 APPswe/PS1dE9 双转基因 AD 小鼠口服非瑟酮可预防学习和记忆缺陷的发展。这与 ERK 磷酸化的增加以及蛋白质羰基化（氧化应激的标志物）的减少相关。重要的是，非瑟酮还能降低对照组和 AD 大脑中细胞周期蛋白依赖性激酶 5 (Cdk5) 激活剂 p35 裂解产物 p25 的水平。 p25 相对于 p35 水平升高会导致 Cdk5 活性失调，从而导致神经炎症和神经变性。这些非瑟酮依赖性变化与额外的抗炎作用相关，包括整体类二十烷酸合成的改变以及 AD 小鼠突触功能标志物的维持。总之，这些结果表明非瑟酮可能为治疗 AD 提供一种新方法。
Alzheimer’s disease (AD) is the most common type of dementia. It is the only one of the top ten causes of death in the USA for which prevention strategies have not been developed. Although AD has traditionally been associated with the deposition of amyloid β plaques and tau tangles, it is becoming increasingly clear that it involves disruptions in multiple cellular systems. Therefore, it is unlikely that hitting a single target will result in significant benefits to patients with AD. An alternative approach is to identify molecules that have multiple biological activities that are relevant to the disease. Fisetin is a small, orally active molecule which can act on many of the target pathways implicated in AD. We show here that oral administration of fisetin to APPswe/PS1dE9 double transgenic AD mice from 3 to 12 months of age prevents the development of learning and memory deficits. This correlates with an increase in ERK phosphorylation along with a decrease in protein carbonylation, a marker of oxidative stress. Importantly, fisetin also reduces the levels of the cyclin-dependent kinase 5 (Cdk5) activator p35 cleavage product, p25, in both control and AD brains. Elevated levels of p25 relative to p35 cause dysregulation of Cdk5 activity leading to neuroinflammation and neurodegeneration. These fisetin-dependent changes correlate with additional anti-inflammatory effects, including alterations in global eicosanoid synthesis, and the maintenance of markers of synaptic function in the AD mice. Together, these results suggest that fisetin may provide a new approach to the treatment of AD.
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影响因子：
16.2
作者：
Cortes-Canteli, Marta;Paul, Justin;Norris, Erin H.;Bronstein, Robert;Ahn, Hyung Jin;Zamolodchikov, Daria;Bhuvanendran, Shivaprasad;Fenz, Katherine M.;Strickland, Sidney
通讯作者：
Strickland, Sidney
影响因子：
4.2
作者：
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通讯作者：
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影响因子：
3.5
作者：
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通讯作者：
Maher, Pamela
影响因子：
4.8
作者：
Choi, Yeon Ho;Lee, Sang-Nam;Yoon, Joo-Heon
通讯作者：
Yoon, Joo-Heon
DOI：
10.1097/01.jnen.0000240472.43038.27
发表时间：
2007-06-01
影响因子：
3.2
作者：
Mohri, Ikuko;Kadoyama, Kelichi;Taniike, Masako
通讯作者：
Taniike, Masako