Lack of human-like extracellular sortilin neuropathology in transgenic Alzheimer's disease model mice and macaques.
Lack of human-like extracellular sortilin neuropathology in transgenic Alzheimer's disease model mice and macaques.
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转基因阿尔茨海默病模型小鼠和猕猴中缺乏类似人类的细胞外分拣蛋白神经病理学
DOI：
10.1186/s13195-018-0370-2
复制
发表时间：
2018-04-24
期刊：
影响因子：
--
通讯作者：
Yan XX
中科院分区：
文献类型：
--
作者：
Zhou FQ;Jiang J;Griffith CM;Patrylo PR;Cai H;Chu Y;Yan XX
阿尔茨海默病（Alzheimer's disease，AD）是一种具有多种病理特征的破坏性神经退行性疾病，其发病过程中存在复杂的细胞/分子相互作用。转基因小鼠和非人灵长类动物被用作AD的机制和转化研究的疾病模型;这些动物模型概括AD型神经病理学的程度是一个重要的问题。近年来研究发现，空泡蛋白分选10蛋白（vacuolar protein sorting 10 protein，Vps 10 p）家族成员sortilin的C-末端片段可存款于人脑神经炎性β-淀粉样蛋白（neuritic β-amyloid，Aβ）斑块中。我们着手探讨AD相关转基因小鼠和非人灵长类动物中是否存在细胞外分拣蛋白神经病理学。来自不同转基因品系和年龄的脑出现明显的脑Aβ沉积，包括约14月龄的β-淀粉样前体蛋白和早老素1双转基因（APP/PS1）小鼠，约8月龄的5个家族性阿尔茨海默病突变转基因（5×FAD）小鼠，约22月龄的三转基因阿尔茨海默病（3×Tg-AD）小鼠，和老年猴（Macaca mulatta和Macaca fascicularis）进行了检查。使用年轻转基因小鼠、中年/老年猴和AD人类的脑样本作为阴性和阳性病理对照。标记AD人脑切片中老年斑的C-末端分拣蛋白抗体，在Aβ沉积的转基因小鼠或老年猴脑切片中未显示细胞外免疫标记。在Western印迹分析中，在转基因小鼠皮质裂解物中检测不到约15 kDa的分拣蛋白片段，但它们出现在对照AD裂解物中。参考它们的人脑对应物，在转基因AD模型小鼠脑中观察到的神经炎斑块代表这种AD病理学标志的不完全形式。神经炎斑块成分的种属差异也表明，在衰老和AD期间，相对于啮齿动物和非人灵长类动物，人脑中的继发性蛋白质病更为复杂。本文的在线版本（10.1186/s13195-018-0370-2）包含补充材料，可供授权用户使用。
Alzheimer’s disease (AD) is a devastating neurodegenerative disorder bearing multiple pathological hallmarks suggestive of complex cellular/molecular interplay during pathogenesis. Transgenic mice and nonhuman primates are used as disease models for mechanistic and translational research into AD; the extent to which these animal models recapitulate AD-type neuropathology is an issue of importance. Putative C-terminal fragments from sortilin, a member of the vacuolar protein sorting 10 protein (Vps10p) family, have recently been shown to deposit in the neuritic β-amyloid (Aβ) plaques in the human brain. We set out to explore if extracellular sortilin neuropathology exists in AD-related transgenic mice and nonhuman primates. Brains from different transgenic strains and ages developed overt cerebral Aβ deposition, including the β-amyloid precursor protein and presenilin 1 double-transgenic (APP/PS1) mice at ~ 14 months of age, the five familial Alzheimer’s disease mutations transgenic (5×FAD) mice at ~ 8 months, the triple-transgenic Alzheimer’s disease (3×Tg-AD) mice at ~ 22 months, and aged monkeys (Macaca mulatta and Macaca fascicularis) were examined. Brain samples from young transgenic mice, middle-aged/aged monkeys, and AD humans were used as negative and positive pathological controls. The C-terminal sortilin antibody, which labeled senile plaques in the AD human cerebral sections, did not display extracellular immunolabeling in the transgenic mouse or aged monkey brain sections with Aβ deposition. In Western blot analysis, sortilin fragments ~ 15 kDa were not detectable in transgenic mouse cortical lysates, but they occurred in control AD lysates. In reference to their human brain counterparts, neuritic plaques seen in transgenic AD model mouse brains represent an incomplete form of this AD pathological hallmark. The species difference in neuritic plaque constituents also indicates more complex secondary proteopathies in the human brain relative to rodents and nonhuman primates during aging and in AD. The online version of this article (10.1186/s13195-018-0370-2) contains supplementary material, which is available to authorized users.
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DOI：
10.1016/j.trci.2017.04.005
发表时间：
2017-09
期刊：
Alzheimer's & dementia (New York, N. Y.)
影响因子：
--
作者：
Gold M
通讯作者：
Gold M
影响因子：
4.2
作者：
Czasch, S;Paul, S;Baumgärtner, W
通讯作者：
Baumgärtner, W
影响因子：
12.7
作者：
Duyckaerts C;Potier MC;Delatour B
通讯作者：
Delatour B
影响因子：
3.4
作者：
Cheng N;Jiao S;Gumaste A;Bai L;Belluscio L
通讯作者：
Belluscio L
DOI：
10.1073/pnas.91.20.9382
发表时间：
1994-09-27
影响因子：
11.1
作者：
GEARING, M;REBECK, GW;MIRRA, SS
通讯作者：
MIRRA, SS