The absence of myelin basic protein promotes neuroinflammation and reduces amyloid β-protein accumulation in Tg-5xFAD mice.
The absence of myelin basic protein promotes neuroinflammation and reduces amyloid β-protein accumulation in Tg-5xFAD mice.
复制标题
髓磷脂碱性蛋白的缺失会促进神经炎症并减少TG-5XFAD小鼠中淀粉样蛋白β-蛋白的积累。
DOI：
10.1186/1742-2094-10-134
复制
发表时间：
2013-11-05
影响因子：
9.3
通讯作者：
Van Nostrand WE
中科院分区：
文献类型：
--
作者：
Ou-Yang MH;Van Nostrand WE
淀粉样蛋白β (Aβ)在大脑中的异常积累在阿尔茨海默病（AD）的发病机制中起重要作用。Aβ单体聚集成低聚物和原纤维，促进神经元功能障碍。这种组装途径受到天然存在的脑分子Aβ伴侣蛋白的影响，该蛋白与Aβ结合并调节其聚集。髓鞘碱性蛋白（Myelin basic protein， MBP）是一种新型的a β伴侣蛋白，是体外a β原纤维组装的有效抑制剂。在本研究中，我们通过将MBP敲除小鼠（MBP-/-）与ad样实质a β病理模型Tg-5xFAD小鼠杂交，确定MBP缺失是否会影响体内a β病理。通过生化和免疫组织化学实验，我们发现双基因Tg-5xFAD/MBP-/-小鼠早期不溶性a β和实质斑块沉积明显减少。在没有MBP的情况下，基因编码的人a - β pp的表达、a - β产生过程中c端片段的水平和细胞内a - β的水平均不受影响。同样，我们没有发现血浆a β或脑脊液a β的显著差异，这表明这些清除途径在双基因Tg-5xFAD/MBP-/-小鼠中没有改变。然而，与Tg-5xFAD小鼠相比，MBP-/-小鼠和双基因Tg-5xFAD/MBP-/-小鼠表现出活性星形胶质细胞和活化的小胶质细胞升高。活化的胶质细胞表达的Aβ降解酶基质金属蛋白酶9 （MMP-9）在Tg-5xFAD/MBP-/-小鼠中显著升高。这些发现表明，MBP的缺失减少了转基因小鼠中Aβ的沉积，这种结果可能是由于神经胶质活化和Aβ降解酶MMP-9的表达增加。
Abnormal accumulation of amyloid β-protein (Aβ) in the brain plays an important role in the pathogenesis \of Alzheimer’s disease (AD). Aβ monomers assemble into oligomers and fibrils that promote neuronal dysfunction. This assembly pathway is influenced by naturally occurring brain molecules, the Aβ chaperone proteins, which bind to Aβ and modulate its aggregation. Myelin basic protein (MBP) was previously identified as a novel Aβ chaperone protein and a potent inhibitor for Aβ fibril assembly in vitro. In this study, we determined whether the absence of MBP would influence Aβ pathology in vivo by breeding MBP knockout mice (MBP-/-) with Tg-5xFAD mice, a model of AD-like parenchymal Aβ pathology. Through biochemical and immunohistochemical experiments, we found that bigenic Tg-5xFAD/MBP-/- mice had a significant decrease of insoluble Aβ and parenchymal plaque deposition at an early age. The expression of transgene encoded human AβPP, the levels of C-terminal fragments generated during Aβ production and the intracellular Aβ were unaffected in the absence of MBP. Likewise, we did not find a significant difference in plasma Aβ or cerebrospinal fluid Aβ, suggesting these clearance routes were unaltered in bigenic Tg-5xFAD/MBP-/- mice. However, MBP-/- mice and bigenic Tg-5xFAD/MBP-/- mice exhibited elevated reactive astrocytes and activated microglia compared with Tg-5xFAD mice. The Aβ degrading enzyme matrix metalloproteinase 9 (MMP-9), which is expressed by activated glial cells, was significantly increased in the Tg-5xFAD/MBP-/- mice. These findings indicate that the absence of MBP decreases Aβ deposition in transgenic mice and that this consequence may result from increased glial activation and expression of MMP-9, an Aβ degrading enzyme.
登录
查看更多内容
影响因子：
4.8
作者：
Davis, J;Xu, F;Van Nostrand, WE
通讯作者：
Van Nostrand, WE
DOI：
10.1196/annals.1342.015
发表时间：
2005-01-01
期刊：
BIOPHYSICS FROM MOLECULES TO BRAIN: IN MEMORY OF RADOSLAV K. ANDJUS
影响因子：
--
作者：
Filipovic, R;Zecevic, N
通讯作者：
Zecevic, N
DOI：
10.1073/pnas.0712197105
发表时间：
2008-02-19
影响因子：
11.1
作者：
Buxbaum, Joel N.;Ye, Zhengyi;Bartfai, Tamas
通讯作者：
Bartfai, Tamas
影响因子：
64.8
作者：
De Strooper, B;Saftig, P;Van Leuven, F
通讯作者：
Van Leuven, F
影响因子：
4.2
作者：
Bartzokis, G;Sultzer, D;Cummings, JL
通讯作者：
Cummings, JL