Accumulation of intraneuronal Abeta correlates with ApoE4 genotype.
Accumulation of intraneuronal Abeta correlates with ApoE4 genotype.
复制标题
DOI：
10.1007/s00401-010-0666-1
复制
发表时间：
2010-05
影响因子：
12.7
通讯作者：
Wirths O
中科院分区：
文献类型：
--
作者：
Christensen DZ;Schneider-Axmann T;Lucassen PJ;Bayer TA;Wirths O
与细胞外斑块和细胞内缠结病理学相反，神经元内Aβ在阿尔茨海默病（AD）中的存在和相关性仍然是一个有争议的问题。人脑组织提供了技术挑战，如死后延迟和不均匀或长期的组织固定，可能会影响免疫组织化学染色。此外，以前关于人脑细胞内Aβ蓄积的研究通常使用靶向Aβ C末端的抗体，并且在所用的预处理方面存在很大差异。为了克服这些不一致性，我们使用高度特异性的N-末端Aβ抗体进行了广泛的参数测试，检测位置1的天冬氨酸，然后开发了用于AD患者石蜡包埋切片中神经元内Aβ检测的最佳染色方案。为了排除该抗体也检测具有相同表位的β-切割的APP C-末端片段（β-CTF，C99），在我们的染色方案中，对过表达C99片段的转基因小鼠的石蜡切片进行染色，没有任何交叉反应性的证据。然后将10例对照组和20例散发性AD患者的皮质和海马组织中神经元内Aβ的染色强度与患者数据（包括性别、Braak分期、斑块负荷和载脂蛋白E（ApoE）基因型）相关。特别是，存在一个或两个ApoE 4等位基因与神经元内Aβ肽蓄积增加密切相关。考虑到ApoE 4是AD的主要遗传风险因素，并参与神经元胆固醇转运，因此很容易推测，AD中神经元内Aβ聚集增加与细胞内转运紊乱有关。本文的在线版本（doi：10.1007/s 00401 -010-0666-1）包含补充材料，可供授权用户使用。
In contrast to extracellular plaque and intracellular tangle pathology, the presence and relevance of intraneuronal Aβ in Alzheimer’s disease (AD) is still a matter of debate. Human brain tissue offers technical challenges such as post-mortem delay and uneven or prolonged tissue fixation that might affect immunohistochemical staining. In addition, previous studies on intracellular Aβ accumulation in human brain often used antibodies targeting the C-terminus of Aβ and differed strongly in the pretreatments used. To overcome these inconsistencies, we performed extensive parametrical testing using a highly specific N-terminal Aβ antibody detecting the aspartate at position 1, before developing an optimal staining protocol for intraneuronal Aβ detection in paraffin-embedded sections from AD patients. To rule out that this antibody also detects the β-cleaved APP C-terminal fragment (β-CTF, C99) bearing the same epitope, paraffin-sections of transgenic mice overexpressing the C99-fragment were stained without any evidence for cross-reactivity in our staining protocol. The staining intensity of intraneuronal Aβ in cortex and hippocampal tissue of 10 controls and 20 sporadic AD cases was then correlated to patient data including sex, Braak stage, plaque load, and apolipoprotein E (ApoE) genotype. In particular, the presence of one or two ApoE4 alleles strongly correlated with an increased accumulation of intraneuronal Aβ peptides. Given that ApoE4 is a major genetic risk factor for AD and is involved in neuronal cholesterol transport, it is tempting to speculate that perturbed intracellular trafficking is involved in the increased intraneuronal Aβ aggregation in AD. The online version of this article (doi:10.1007/s00401-010-0666-1) contains supplementary material, which is available to authorized users.
登录
查看更多内容
影响因子：
6.1
作者：
Almeida, CG;Tampellini, D;Gouras, GK
通讯作者：
Gouras, GK
影响因子：
82.9
作者：
Deane, R;Yan, SD;Zlokovic, B
通讯作者：
Zlokovic, B
影响因子：
12.7
作者：
Breyhan, Henning;Wirths, Oliver;Bayer, Thomas A.
通讯作者：
Bayer, Thomas A.
影响因子：
5.3
作者：
Bales, Kelly R.;Liu, Feng;Paul, Steven M.
通讯作者：
Paul, Steven M.
影响因子：
2.5
作者：
D'Andrea, MR;Nagele, RG;Andrade-Gordon, P
通讯作者：
Andrade-Gordon, P