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Amyloid-β interrupts canonical Sonic hedgehog signaling by distorting primary cilia structure

机译：淀粉样蛋白-β通过扭曲初级纤毛结构来中断典型的声波刺猬信号。

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Primary cilia are small non-motile microtubule and cell membrane protrusions expressed on most vertebrate cells, including cortical and hippocampal neurons. These small organelles serve as sensory structures sampling the extracellular environment and reprogramming the transcriptional machinery in response to environmental change. Primary cilia are decorated with a variety of receptor proteins and are necessary for specific signaling cascades such as the Sonic hedgehog (Shh) pathway. Disrupting cilia structure or function results in a spectrum of diseases collectively referred to as ciliopathies. Common to human ciliopathies is cognitive impairment, a symptom also observed in Alzheimer’s disease (AD). One hallmark of AD is accumulation of senile plaques composed of neurotoxic Amyloid-β (Aβ) peptide. The Aβ peptide is generated by the proteolytic cleavage of the amyloid precursor protein (APP). We set out to determine if Aβ affects primary cilia structure and the Shh signaling cascade. We utilized in vitro cell-based assays in combination with fluorescent confocal microscopy to address our study goals. Shh signaling and cilia structure was studied using two different cell lines, mouse NIH3T3 and human HeLa cells. To investigate how Aβ levels affect Shh signaling and cilia structure in these cells, we utilized naturally secreted Aβ as well as synthetic Aβ. Effects on Shh signaling were assessed by luciferase activity while cilia structure was analyzed by fluorescent microscopy. Here, we report that APP localizes to primary cilia and Aβ treatment results in distorted primary cilia structure. In addition, we demonstrate that Aβ treatment interrupts canonical Shh signal transduction. Overall, our study illustrates that Aβ can alter primary cilia structure suggesting that elevated Aβ levels, like those observed in AD patients, could have similar effects on neuronal primary cilia in the brain. Additionally, our study suggests that Aβ impairs the Shh signaling pathway. Together our findings shed light on two novel targets for future AD therapeutics.
机译：原发纤毛是在大多数脊椎动物细胞（包括皮层和海马神经元）上表达的小的非活动性微管和细胞膜突起。这些小细胞器充当感官结构，对细胞外环境进行采样并响应环境变化对转录机制进行重新编程。初级纤毛装饰有多种受体蛋白，对于特定的信号级联反应（如Sonic刺猬（Shh）途径）是必需的。破坏纤毛的结构或功能会导致一系列疾病，统称为纤毛病。人类纤毛病常见的是认知障碍，这也是阿尔茨海默氏病（AD）的一种症状。 AD的一个特征是由神经毒性淀粉样-β（Aβ）肽组成的老年斑的积累。 Aβ肽是通过淀粉样蛋白前体蛋白（APP）的蛋白水解切割产生的。我们着手确定Aβ是否影响初级纤毛结构和Shh信号级联。我们结合荧光共聚焦显微镜，利用了基于细胞的体外检测方法来实现我们的研究目标。 Shh信号和纤毛结构使用两种不同的细胞系，小鼠NIH3T3和人HeLa细胞进行了研究。为了研究Aβ水平如何影响这些细胞中的Shh信号传导和纤毛结构，我们利用了自然分泌的Aβ以及合成的Aβ。通过荧光素酶活性评估对Shh信号的影响，同时通过荧光显微镜分析纤毛结构。在这里，我们报道APP定位于原发性纤毛，而Aβ治疗导致原发性纤毛结构变形。此外，我们证明了Aβ治疗可中断规范的Shh信号转导。总体而言，我们的研究表明Aβ可以改变原发性纤毛结构，提示Aβ水平升高（如在AD患者中观察到的）可能会对大脑神经元原发性纤毛产生类似的影响。此外，我们的研究表明Aβ会破坏Shh信号通路。我们的发现共同阐明了未来AD治疗的两个新目标。

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