Ceramides in Alzheimer's Disease: Key Mediators of Neuronal Apoptosis Induced by Oxidative Stress and Aβ Accumulation.
Ceramides in Alzheimer's Disease: Key Mediators of Neuronal Apoptosis Induced by Oxidative Stress and Aβ Accumulation.
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DOI：
10.1155/2015/346783
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发表时间：
2015
影响因子：
--
通讯作者：
Šimić G
中科院分区：
文献类型：
--
作者：
Jazvinšćak Jembrek M;Hof PR;Šimić G
阿尔茨海默病（Alzheimer's disease，AD）是最常见的慢性进行性神经退行性疾病，其特征是细胞外沉积淀粉样β肽（amyloid β-peptides，Aβ）和细胞内沉积过度磷酸化的tau蛋白（phospho-tau）。神经酰胺是鞘脂代谢的主要分子和脂质第二信使，通过Aβ的产生与AD的进展和病理学相关。神经酰胺水平的提高通过稳定β-分泌酶直接增加Aβ，β-分泌酶是Aβ前体蛋白（APP）淀粉样蛋白形成过程中的关键酶。作为正反馈环，生成的寡聚体和纤维状Aβ通过激活鞘磷脂酶（催化鞘磷脂分解代谢为神经酰胺）诱导神经酰胺水平进一步升高。证据也支持神经酰胺在神经元凋亡中的重要作用。神经酰胺可引发一系列生化改变，最终通过多种机制导致神经元死亡，包括线粒体的去极化和透化、活性氧（ROS）产生增加、细胞色素c释放、Bcl-2耗竭和caspase-3激活，主要通过调节细胞内信号传导，特别是沿着与Akt/PKB激酶和促分裂原活化蛋白激酶（MAPK）相关的通路。本文综述了神经酰胺在氧化应激驱动的神经元凋亡中的作用以及与Aβ在神经元变性级联反应中的相互作用。
Alzheimer's disease (AD), the most common chronic and progressive neurodegenerative disorder, is characterized by extracellular deposits of amyloid β-peptides (Aβ) and intracellular deposits of hyperphosphorylated tau (phospho-tau) protein. Ceramides, the major molecules of sphingolipid metabolism and lipid second messengers, have been associated with AD progression and pathology via Aβ generation. Enhanced levels of ceramides directly increase Aβ through stabilization of β-secretase, the key enzyme in the amyloidogenic processing of Aβ precursor protein (APP). As a positive feedback loop, the generated oligomeric and fibrillar Aβ induces a further increase in ceramide levels by activating sphingomyelinases that catalyze the catabolic breakdown of sphingomyelin to ceramide. Evidence also supports important role of ceramides in neuronal apoptosis. Ceramides may initiate a cascade of biochemical alterations, which ultimately leads to neuronal death by diverse mechanisms, including depolarization and permeabilization of mitochondria, increased production of reactive oxygen species (ROS), cytochrome c release, Bcl-2 depletion, and caspase-3 activation, mainly by modulating intracellular signalling, particularly along the pathways related to Akt/PKB kinase and mitogen-activated protein kinases (MAPKs). This review summarizes recent findings related to the role of ceramides in oxidative stress-driven neuronal apoptosis and interplay with Aβ in the cascade of events ending in neuronal degeneration.
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影响因子：
7.4
作者：
Circu, Magdalena L.;Aw, Tak Yee
通讯作者：
Aw, Tak Yee
DOI：
10.1016/s0140-6736(20)32205-4
发表时间：
2021-04-24
期刊：
Lancet (London, England)
影响因子：
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作者：
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影响因子：
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作者：
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