Alterations of the sphingolipid pathway in Alzheimer's disease: new biomarkers and treatment targets?
Alterations of the sphingolipid pathway in Alzheimer's disease: new biomarkers and treatment targets?
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DOI：
10.1007/s12017-010-8121-y
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发表时间：
2010-12
影响因子：
3.5
通讯作者：
Lyketsos, Constantine G.
中科院分区：
文献类型：
--
作者：
Mielke, Michelle M.;Lyketsos, Constantine G.
阿尔茨海默病（AD）是最常见的神经退行性疾病，其公共卫生负担在本世纪中期有爆发的危险。目前FDA批准的AD治疗（例如胆碱酯酶抑制剂、NMDA受体激动剂）不提供“治愈”，而是暂时缓解一些个体的症状。其他可用的治疗方法很少，有效性有限，因此需要其他途径。鞘脂代谢是一个动态的过程，调节许多生物活性代谢物的形成，或在细胞信号传导和凋亡中至关重要的第二信使。在大脑中，鞘脂的适当平衡对于正常的神经元功能是必不可少的，正如许多严重的大脑疾病所证明的那样，这些疾病是由于控制鞘脂代谢的酶缺乏的结果。实验室和动物研究表明鞘脂促进淀粉样β蛋白产生和阿尔茨海默病发病机制的直接和间接机制，但很少有研究将这些发现转化为人类。建立在实验室和动物证据表明鞘脂代谢在AD的重要性，这篇综述强调了相关的转化研究纳入和扩大人类的基本发现。首先简要介绍了AD中鞘脂（鞘磷脂、神经酰胺和硫苷脂）的生物学概况，然后回顾了人体研究，包括尸检研究、临床和流行病学研究。最后，外周神经酰胺在AD发病机制中的潜在作用进行了讨论，以及可能使用的鞘脂作为AD的生物标志物。
The public health burden of Alzheimer disease (AD), the most common neurodegenerative disease, threatens to explode in the middle of this century. Current FDA-approved AD treatments (e.g. cholinesterase inhibitors, NMDA-receptor agonists) do not provide a “cure”, but rather a transient alleviation of symptoms for some individuals. Other available therapies are few and of limited effectiveness so additional avenues are needed. Sphingolipid metabolism is a dynamic process that modulates the formation of a number of bioactive metabolites, or second messengers critical in cellular signaling and apoptosis. In brain, the proper balance of sphingolipids is essential for normal neuronal function, as evidenced by a number of severe brain disorders that are the result of deficiencies in enzymes that control sphingolipid metabolism. Laboratory and animals studies suggest both direct and indirect mechanisms by which sphingolipids contribute to amyloid-beta production and Alzheimer pathogenesis but few studies have translated these findings to humans. Building on the laboratory and animal evidence demonstrating the importance of sphingolipid metabolism in AD, this review highlights relevant translational research incorporating and expanding basic findings to humans. A brief biological overview of sphingolipids (sphingomyelins, ceramides, and sulfatides) in AD is first described, followed by a review of human studies including post-mortem studies, clinical and epidemiological studies. Lastly, the potential role of peripheral ceramides in AD pathogenesis is discussed, as well as the possible use of sphingolipids as biomarkers for AD.
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影响因子：
4.2
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