尼曼-匹克C型病与阿尔茨海默病：淀粉样前体蛋白与内体的关联愈发紧密。
Niemann-Pick Type C disease and Alzheimer's disease: the APP-endosome connection fattens up.
作者信息
Nixon Ralph A
机构信息
Department of Psychiatry, New York University School of Medicine, Center for Dementia Research, Nathan Kline Institute, Orangeburg, New York 10962, USA.
出版信息
Am J Pathol. 2004 Mar;164(3):757-61. doi: 10.1016/S0002-9440(10)63163-X.
Abstract
Niemann-Pick Type C (NPC) is an inherited neurodegenerative disease of childhood and adolescence that develops from a failure of cholesterol trafficking within the endosomal-lysosomal pathway. Although NPC differs in major respects from Alzheimer's disease (AD), intriguing parallels exist in the cellular pathology of these two diseases, including neurofibrillary tangle formation, prominent lysosome system dysfunction, and influences of apolipoprotein E epsilon4 genotype. Added to these similarities are new findings that some neuronal populations develop abnormalities of endosomes resembling those seen at the earliest stages of AD and also accumulate beta-cleaved amyloid precursor protein (APP) and Abeta peptides within endosomes. In this commentary, the common features of endosome dysfunction are reviewed. Emerging evidence that endosome dysfunction may lead to beta-amyloidogenic APP processing or neurodegeneration by several different means is discussed.
摘要
尼曼-皮克C型病（NPC）是一种发生于儿童期和青少年期的遗传性神经退行性疾病，由内体-溶酶体途径内胆固醇转运失败所致。尽管NPC在主要方面与阿尔茨海默病（AD）不同，但这两种疾病在细胞病理学上存在有趣的相似之处，包括神经原纤维缠结形成、显著的溶酶体系统功能障碍以及载脂蛋白Eε4基因型的影响。除了这些相似之处外，还有新的发现，即一些神经元群体出现内体异常，类似于在AD最早阶段所见，并且在内体内积累β-裂解淀粉样前体蛋白（APP）和Aβ肽。在这篇评论中，我们回顾了内体功能障碍的共同特征。讨论了新出现的证据，即内体功能障碍可能通过几种不同方式导致β-淀粉样蛋白生成性APP加工或神经退行性变。
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本文引用的文献
1
Intracellular accumulation of amyloidogenic fragments of amyloid-beta precursor protein in neurons with Niemann-Pick type C defects is associated with endosomal abnormalities.在患有尼曼-匹克C型缺陷的神经元中，淀粉样前体蛋白的淀粉样生成片段的细胞内积累与内体异常有关。
Am J Pathol. 2004 Mar;164(3):975-85. doi: 10.1016/s0002-9440(10)63185-9.
2
Alix, a protein regulating endosomal trafficking, is involved in neuronal death.Alix是一种调节内体运输的蛋白质，参与神经元死亡。
J Biol Chem. 2004 Jan 16;279(3):2046-52. doi: 10.1074/jbc.M309243200. Epub 2003 Oct 29.
3
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4
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Clin Genet. 2003 Oct;64(4):269-81. doi: 10.1034/j.1399-0004.2003.00147.x.
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Eur J Neurosci. 2003 Aug;18(3):473-85. doi: 10.1046/j.1460-9568.2003.02757.x.
6
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7
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8
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9
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J Biol Chem. 2003 Aug 15;278(33):31261-8. doi: 10.1074/jbc.M304122200. Epub 2003 May 20.
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