Role of p38/MAPKs in Alzheimer's disease: implications for amyloid beta toxicity targeted therapy
Role of p38/MAPKs in Alzheimer's disease: implications for amyloid beta toxicity targeted therapy
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DOI：
10.1515/revneuro-2018-0008
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发表时间：
2019-01-01
影响因子：
4.1
通讯作者：
Rezaei, Nima
中科院分区：
文献类型：
--
作者：
Kheiri, Ghazaleh;Dolatshahi, Mahsa;Rezaei, Nima
无数的环境和遗传因素，以及老化的生理过程，有助于阿尔茨海默病（AD）的病理。神经炎症是并且一直是关注的焦点，作为引发AD的许多潜在病理学的共同途径。淀粉样蛋白β（A β）毒性、增加的β-淀粉样蛋白表达、tau蛋白过度磷酸化、诱导凋亡和失调的自噬是其他机制中的一种，其部分地与丝裂原活化蛋白激酶（MAPK）和MAPK信号传导的活化纠缠在一起并被解释。p38 MAPK是该家族中A β诱导毒性的最重要调节因子。p38诱导NF-κ B活化、谷氨酸兴奋毒性和突触可塑性的破坏，这是所有证明p38 MAPK作为打破恶性AP毒性循环的潜在靶点的其他含义。直到最近，许多体内和体外研究已经研究了p38 MAPK抑制剂在AD中的作用。吡啶基咪唑化合物SB 202190和SB 203580在体内显示出有希望的抗凋亡结果。MW 108抑制p38的激活，并能够延缓动物模型中的认知能力下降。具有抗炎、抗氧化和抗凋亡特征的PD 169316在体内具有改善的空间记忆。来自茶树（绿色茶）的天然化合物、来自橄榄油的多酚、来自茶树的松属素和葛根素提取物的黄酮类化合物已显示出由p38 MAPK抑制介导的强抗凋亡特征。由于中枢神经系统副作用或与其他激酶的交叉反应，这些药物靶点的使用受到限制，预测这些药物在临床试验中的疗效较低。
A myriad of environmental and genetic factors, as well as the physiologic process of aging, contribute to Alzheimer's disease (AD) pathology. Neuroinflammation is and has been a focus of interest, as a common gateway for initiation of many of the underlying pathologies of AD. Amyloid beta (A beta) toxicity, increasing RAGE expression, tau hyperphosphorylation, induction of apoptosis, and deregulated autophagy are among other mechanisms, partly entangled and being explained by activation of mitogen-activated protein kinase (MAPK) and MAPK signaling. p38 MAPK is the most essential regulator of A beta induced toxicity from this family. p38 induces NF-kappa B activation, glutamate excitotoxicity, and disruption of synaptic plasticity, which are other implications of all justifying the p38 MAPK as a potential target to break the vicious AP toxicity cycle. Until recently, many in vivo and in vitro studies have investigated the effects of p38 MAPK inhibitors in AD. The pyridinyl imidazole compounds SB202190 and SB203580 have shown promising anti-apoptotic results in vivo. MW108 inhibits activation of p38 and is able to postpone cognitive decline in animal models. The PD169316, with anti-inflammatory, anti-oxidative, and anti-apoptotic features, has improved spatial memory in vivo. Natural compounds from Camellia sinensis (green tea), polyphenols from olive oil, pinocembrin from propolis, and the puerarine extract isoflavones, have shown strong antiapoptotic features, mediated by p38 MAPK inhibition. Use of these drug targets is limited due to central nervous system side effects or cross-reactivity with other kinases, predicting the low efficacy of these drugs in clinical trials.