脑内淀粉样前体蛋白（APP）与特异性蛋白1（SP1）的共定位、分布及其与淀粉样变的关系
Co-localization and distribution of cerebral APP and SP1 and its relationship to amyloidogenesis.
作者信息
Brock Brian, Basha Riyaz, DiPalma Katie, Anderson Amy, Harry G Jean, Rice Deborah C, Maloney Bryan, Lahiri Debomoy K, Zawia Nasser H
机构信息
Neurotoxicology and Epigenomics Laboratory, Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI 02881, USA.
出版信息
J Alzheimers Dis. 2008 Feb;13(1):71-80. doi: 10.3233/jad-2008-13108.
Abstract
Alzheimer's disease is characterized by amyloid-beta peptide (Abeta)-loaded plaques in the brain. Abeta is a cleavage fragment of amyloid-beta protein precursor (APP) and over production of APP may lead to amyloidogenesis. The regulatory region of the APP gene contains consensus sites recognized by the transcription factor, specificity protein 1 (SP1), which has been shown to be required for the regulation of APP and Abeta. To understand the role of SP1 in APP biogenesis, herein we have characterized the relative distribution and localization of SP1, APP, and Abeta in various brain regions of rodent and primate models using immunohistochemistry. We observed that overall distribution and cellular localization of SP1, APP, and Abeta are similar and neuronal in origin. Their distribution is abundant in various layers of neocortex, but restricted to the Purkinje cell layer of the cerebellum, and the pyramidal cell layer of hippocampus. These findings suggest that overproduction of Abeta in vivo may be associated with transcriptional pathways involving SP1 and the APP gene.
摘要
阿尔茨海默病的特征是大脑中存在载有β淀粉样肽（Aβ）的斑块。Aβ是淀粉样β蛋白前体（APP）的裂解片段，APP的过量产生可能导致淀粉样蛋白生成。APP基因的调控区域包含转录因子特异性蛋白1（SP1）识别的共有位点，已证明该转录因子是调节APP和Aβ所必需的。为了了解SP1在APP生物合成中的作用，我们在此使用免疫组织化学对啮齿动物和灵长类动物模型不同脑区中SP1、APP和Aβ的相对分布及定位进行了表征。我们观察到，SP1、APP和Aβ的总体分布及细胞定位相似且起源于神经元。它们在新皮质的各层中分布丰富，但局限于小脑的浦肯野细胞层和海马体的锥体细胞层。这些发现表明，体内Aβ的过量产生可能与涉及SP1和APP基因的转录途径有关。
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J Neurosci. 2008 Jan 2;28(1):3-9. doi: 10.1523/JNEUROSCI.4405-07.2008.
2
Sp3 and sp4 transcription factor levels are increased in brains of patients with Alzheimer's disease.阿尔茨海默病患者大脑中Sp3和Sp4转录因子水平升高。
Neurodegener Dis. 2007;4(6):413-23. doi: 10.1159/000107701. Epub 2007 Oct 9.
3
How and when environmental agents and dietary factors affect the course of Alzheimer's disease: the "LEARn" model (latent early-life associated regulation) may explain the triggering of AD.环境因素和饮食因素如何以及何时影响阿尔茨海默病的病程：“LEARn”模型（潜在的早期生活相关调节）或许可以解释阿尔茨海默病的发病机制。
Curr Alzheimer Res. 2007 Apr;4(2):219-28. doi: 10.2174/156720507780362164.
4
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Curr Alzheimer Res. 2006 Dec;3(5):475-83. doi: 10.2174/156720506779025224.
5
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Neurobiol Aging. 2007 Aug;28(8):1221-30. doi: 10.1016/j.neurobiolaging.2006.05.029. Epub 2006 Jul 3.
6
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J Mol Neurosci. 2006;29(1):65-80. doi: 10.1385/JMN:29:1:65.
7
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8
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Neuropathol Appl Neurobiol. 2005 Apr;31(2):170-80. doi: 10.1111/j.1365-2990.2004.00624.x.
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