The Aβ Containing Brain Extracts Having Different Effects in Alzheimer's Disease Transgenic Caenorhabditis elegans and Mice.
The Aβ Containing Brain Extracts Having Different Effects in Alzheimer's Disease Transgenic Caenorhabditis elegans and Mice.
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含 Aβ 的脑提取物对阿尔茨海默氏病转基因秀丽隐杆线虫和小鼠有不同的作用
DOI：
10.3389/fnagi.2018.00208
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发表时间：
2018
影响因子：
4.8
通讯作者：
Huang F
中科院分区：
文献类型：
--
作者：
Yang Y;Wang M;Yang P;Wang Z;Huang L;Xu J;Wang W;Yu M;Bu L;Fei J;Huang F
背景：富含β-折叠的淀粉样蛋白在老年斑中的沉积是阿尔茨海默病（AD）的一个病理特征，据认为它会导致神经元功能障碍。先前的研究强烈表明，脑内输注含有聚集的β-淀粉样蛋白（Aβ）的脑提取物能够诱导脑淀粉样变性，从而在啮齿动物和非人灵长类动物中导致神经元损伤和临床异常，这让人联想到一种类朊病毒机制。朊病毒疾病已在食用被朊病毒污染的食物的病例中有记载。
方法：我们通过免疫组织化学、蛋白质印迹和行为测试，研究了在非易感和易感宿主小鼠中，口服富含Aβ的脑提取物是否可能导致Aβ的脑传播。还将脑提取物提供给AD转基因秀丽隐杆线虫，并在检测Aβ淀粉样蛋白后绘制麻痹曲线。然后对线虫进行RNA测序，并在诱导麻痹中使用相关失调基因的抑制剂。
结果：口服AD脑提取物或正常脑提取物既没有加重也没有减轻受体淀粉样前体蛋白/早老素1（APP/PS1）小鼠的Aβ负荷、胶质细胞激活或异常行为。然而，在用富含Aβ或正常脑提取物处理的线虫中检测到AD病理有显著改善，这归因于脑提取物的热敏感成分。CL4176线虫的转录组测序表明，脑提取物可通过多种途径延迟线虫麻痹，包括泛素介导的蛋白水解和转化生长因子β（TGF -β）信号通路。泛素蛋白酶体系统和TGF -β信号通路的抑制剂显著阻断了脑提取物对线虫麻痹的抑制作用。
结论：我们的结果表明，朊病毒蛋白病的系统性传播机制可能不适用于β-淀粉样蛋白，至少在口服给药方面是如此。然而，脑提取物通过TGF -β信号通路和泛素介导的蛋白水解部分地显著改善了AD转基因线虫中的AD病理，这表明哺乳动物组织中的一些天然内源性成分可以抵抗Aβ毒性。
Background: The deposition of β-sheet rich amyloid in senile plaques is a pathological hallmark of Alzheimer’s disease (AD), which is thought to cause neuronal dysfunction. Previous studies have strongly implicated that intracerebral infusion of brain extract containing aggregated β-amyloid (Aβ) is able to induce cerebral amyloidosis thus causing neuronal damage and clinical abnormalities in rodents and nonhuman primates, which are reminiscent of a prion-like mechanism. Prion disease has been documented in cases of prion-contaminated food consumption. Methods: We investigated whether cerebral transmission of Aβ was possible via oral administration of Aβ-rich brain extract in non-susceptible and susceptible host mice by immunohistochemistry, western blotting and behavior tests. Also brain extracts were supplied to AD transgenic Caenorhabditis elegans, and paralysis curve were conducted, following detection of Aβ amyloid. RNA sequencing of nematodes was applied then inhibitors for relevant dysregulated genes were used in the paralysis induction. Results: The oral treatment of AD brain extract or normal brain extract neither aggravated nor mitigated the Aβ load, glial activation or the abnormal behaviors in recipient Amyloid precursor protein/presenilin 1 (APP/PS1) mice. Whereas, a significant improvement of AD pathology was detected in worms treated with Aβ-rich or normal brain extracts, which was attributable to the heat-sensitive components of brain extracts. Transcriptome sequencing of CL4176 nematodes suggested that brain extracts could delay worm paralysis through multiple pathways, including ubiquitin mediated proteolysis and Transforming growth factor β (TGF-β) signaling pathway. Inhibitors of the ubiquitin proteasome system and the TGF-β signaling pathway significantly blocked the suppressive effects of brain extracts on worm paralysis. Conclusions: Our results suggest that systemic transmissible mechanisms of prion proteopathy may not apply to β amyloid, at least in terms of oral administration. However, brain extracts strongly ameliorated AD pathology in AD transgenic nematodes partially through TGF-β signaling pathway and ubiquitin mediated proteolysis, which indicated that some natural endogenous components in the mammalian tissues could resist Aβ toxicity.
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影响因子：
56.9
作者：
Meyer-Luehmann, Melanie;Coomaraswamy, Janaky;Jucker, Mathias
通讯作者：
Jucker, Mathias
影响因子：
5.1
作者：
Haque, Rizwanul;Nazir, Aamir
通讯作者：
Nazir, Aamir
影响因子：
3.5
作者：
Hong, Xiaoqi;Liu, Jie;Huang, Fang
通讯作者：
Huang, Fang
影响因子：
5.3
作者：
Caccamo, Antonella;De Pinto, Vito;Oddo, Salvatore
通讯作者：
Oddo, Salvatore
DOI：
10.1073/pnas.0903200106
发表时间：
2009-08-04
影响因子：
11.1
作者：
Eisele, Yvonne S.;Bolmont, Tristan;Jucker, Mathias
通讯作者：
Jucker, Mathias