ROCK1 Is Associated with Alzheimer's Disease-Specific Plaques, as well as Enhances Autophagosome Formation But not Autophagic Aβ Clearance.
ROCK1 Is Associated with Alzheimer's Disease-Specific Plaques, as well as Enhances Autophagosome Formation But not Autophagic Aβ Clearance.
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DOI：
10.3389/fncel.2016.00253
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发表时间：
2016
影响因子：
5.3
通讯作者：
Ren RJ
中科院分区：
文献类型：
--
作者：
Hu YB;Zou Y;Huang Y;Zhang YF;Lourenco GF;Chen SD;Halliday GM;Wang G;Ren RJ
阿尔茨海默病（AD）是人群中最普遍的晚期痴呆形式，其特征在于淀粉样蛋白斑块形成和增加的tau沉积，其由Rho相关卷曲螺旋激酶1（ROCK 1）调节。在这项研究中，我们进一步分析ROCK 1是否调节淀粉样前体蛋白（APP）的代谢。我们发现，ROCK 1与AD患者的成熟淀粉样蛋白-β（Aβ）斑块共定位，因为ROCK 1增强淀粉样蛋白生成途径，并且ROCK 1介导的自噬增强AD细胞模型中Aβ的细胞内积累（通过增加ROCK 1和降低Beclin 1蛋白水平以及AD APP/PS1小鼠模型前额叶皮质中神经元自噬体积累证实）。在体外过表达ROCK 1导致Aβ分泌减少和自噬相关分子表达增加。ROCK 1与自噬启动子Beclin 1相互作用，增强Aβ的细胞内积累。相反，APP/Aβ的过表达促进ROCK 1的表达。我们的数据表明ROCK 1参与调节Aβ分泌、APP脱落和自噬体积累，并且ROCK 1比其他激酶更可能成为AD治疗的靶向酶。
Alzheimer’s disease (AD) is the most prevalent form of late-life dementia in the population, characterized by amyloid plaque formation and increased tau deposition, which is modulated by Rho-associated coiled-coil kinase 1 (ROCK1). In this study, we further analyze whether ROCK1 regulates the metabolism of amyloid precursor protein (APP). We show that ROCK1 is colocalized with mature amyloid-β (Aβ) plaques in patients with AD, in that ROCK1 enhances the amyloidogenic pathway, and that ROCK1 mediated autophagy enhances the intracellular buildup of Aβ in a cell model of AD (confirmed by increased ROCK1 and decreased Beclin 1 protein levels, with neuronal autophagosome accumulation in prefrontal cortex of AD APP/PS1 mouse model). In vitro over-expression of ROCK1 leads to a decrease in Aβ secretion and an increase in the expression of autophagy-related molecules. ROCK1 interacts with Beclin1, an autophagy initiator, and enhances the intracellular accumulation of Aβ. Reciprocally, overexpression of APP/Aβ promotes ROCK1 expression. Our data suggest ROCK1 participates in regulating Aβ secretion, APP shedding and autophagosome accumulation, and that ROCK1, rather than other kinases, is more likely to be a targetable enzyme for AD therapy.
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