Brain Iron Dysregulation and the Risk of Ageing White Matter Lesions
Brain Iron Dysregulation and the Risk of Ageing White Matter Lesions
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DOI：
10.1007/s12017-011-8161-y
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发表时间：
2011-12-01
影响因子：
3.5
通讯作者：
Ince, Paul G.
中科院分区：
文献类型：
--
作者：
Gebril, Ola H.;Simpson, J. E.;Ince, Paul G.
白色病变（WML）或脑白质疏松症是老年人脑成像的主要特征，其患病率随年龄增加而增加。WML的临床效果随着在认知功能中检测到的主要损害而变化，严重抑郁症和运动障碍的风险增加。虽然血管合并症已被发现是这些大脑中的主要变化，但活性氧（ROS）产生增加可能是这些病变的风险因素，元素铁是ROS产生的潜在因素。本研究主要从铁、铁调节蛋白和铁代谢相关基因的RNA表达变化三个方面进行研究。使用三组样品：WML、作为疾病对照的来自病灶WM的正常区域[NAWM（L）]和来自对照脑的正常WM [NAWM（C）]。使用已知的Perl反应进行三价铁染色。对白色物质进行铜蓝蛋白（Cp）、血色病（HFE）和转铁蛋白受体（TfR）的免疫组织化学（IHC）。使用双抗体IHC进行HFE和Cp的细胞定位。从WML、NAWM（L）和NAWM（C）中提取全基因组RNA，并对HFE、TF、TfR、血浆铜蓝蛋白、铁蛋白和膜铁蛋白进行QPCR。三价铁染色显示WML中弥漫性铁染色增加，其次是NAWM（L），最少的组是NAWM（C）。免疫组化结果显示，HFE和CP在损伤WM中的表达增加，而TfR在各组间无变化。在WML和对照样品中，HFE与血管内皮和小胶质细胞共定位，而Cp与小胶质细胞共定位，并且在星形胶质细胞中显示出一定的表达。使用QPCR的mRNA表达表明有利于减少细胞内铁流入、增加亚铁氧化和增加铁从细胞输出的模式。铁代谢似乎在WML的大脑中发生了变化，这些大脑中元素铁的增加以及自由氧化自由基的产生增加可能代表了衰老WML发展的增强因素。
White matter lesions (WML) or leukoaraiosis is a major feature in cerebral imaging of older people, and their prevalence increases with age. The clinical effects of WML vary with the main impairment being detected in the cognitive functions, increased risk of severe depression and motor impairment. Although vascular comorbidities have been found to be the main changes in these brains, increased production of reactive oxygen species (ROS) could represent a risk factor for these lesions with elemental iron being a potential factor for ROS production. This study focuses on changes in iron, iron-regulating proteins and RNA expression of iron metabolism genes. Three groups of samples were used: WML, normal areas from lesional WM [NAWM (L)] as disease control and normal WM from control brains [NAWM(C)]. Ferric iron staining was undertaken using known Perl's reaction. Immunohistochemistry (IHC) of white matter for ceruloplasmin (Cp), haemochromatosis (HFE) and transferrin receptor (TfR) was done. Cellular localization of HFE and Cp was performed using dual-antibody IHC. Whole-genome RNA was extracted from WML, NAWM (L) and NAWM(C), and QPCR for HFE, TF, TfR, ceruloplasmin, ferritin and ferroportin was performed. Ferric iron staining shows increased diffuse iron staining among WML, followed by NAWM (L) and the least group being NAWM(C). IHC shows increased HFE and CP expression in lesional WM, while TfR shows no changes among the groups. HFE colocalized with vascular endothelium and microglia in WML and control samples, while Cp colocalized with microglia and some expression was shown by astrocytes. The mRNA expression using QPCR suggests a pattern that favours decreased intracellular iron influx, increased ferrous oxidation and increased iron export from the cells. Iron metabolism seems to be changed in brains with WML, increased elemental iron in these brains and in turn increased production of free oxidative radicals could represent a potentiating factor for the development of ageing WML.