Impairment of ciliary dynamics in an APP knock-in mouse model of Alzheimer's disease.
Impairment of ciliary dynamics in an APP knock-in mouse model of Alzheimer's disease.
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DOI：
10.1016/j.bbrc.2022.04.050
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发表时间：
2022-04
影响因子：
3.1
通讯作者：
Yuki Kobayashi;Shogo Kohbuchi;Noriko Koganezawa;Yuko Sekino;T. Shirao;T. Saido;T. Saito;Yumiko Saito
中科院分区：
文献类型：
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作者：
Yuki Kobayashi;Shogo Kohbuchi;Noriko Koganezawa;Yuko Sekino;T. Shirao;T. Saido;T. Saito;Yumiko Saito
初级纤毛是一种特殊的基于微管的感觉细胞器，从几乎所有细胞类型的细胞体延伸出来。神经元初级纤毛具有自己独特的信号库，对整个成年期神经元的完整性和神经元连通性的维持至关重要。纤毛结构和纤毛信号的功能障碍与多种遗传综合征有关，称为纤毛病。人类纤毛病的特征之一是记忆和认知障碍，这在阿尔茨海默病（AD）中也有观察到。淀粉样蛋白β肽（Aβ）是通过淀粉样前体蛋白（APP）的蛋白水解加工产生的，而Aβ在大脑中的积累被认为是AD发病过程中的早期毒性事件。为了评估Aβ水平升高对初级纤毛的影响，我们在APP敲入AD模型（appnl - g - f小鼠）中比较了与野生型小鼠相比海马神经元的纤毛动力学。野生型小鼠CA1、CA3和齿状回（DG）的神经元纤毛长度随着年龄的增长而显著增加。在appnl - g - f小鼠中，这种延长在DG中检测到，而在CA1和CA3中没有，在CA1和CA3中观察到更多的Aβ积累。我们进一步证明，Aβ1-42处理减少了hTERT-RPE1细胞和游离大鼠海马神经元的纤毛长度。越来越多的证据表明，纤毛长度的减少与突触连通性和树突复杂性的扰动有关。因此，我们的观察结果提出了重要的可能性，即神经元纤毛的结构改变可能在阿尔茨海默病的发展中起作用。
The primary cilium is a specialized microtubule-based sensory organelle that extends from the cell body of nearly all cell types. Neuronal primary cilia, which have their own unique signaling repertoire, are crucial for neuronal integrity and the maintenance of neuronal connectivity throughout adulthood. Dysfunction of cilia structure and ciliary signaling is associated with a variety of genetic syndromes, termed ciliopathies. One of the characteristic features of human ciliopathies is impairment of memory and cognition, which is also observed in Alzheimer's disease (AD). Amyloid β peptide (Aβ) is produced through the proteolytic processing of amyloid precursor protein (APP), and Aβ accumulation in the brain is proposed to be an early toxic event in the pathogenesis of AD. To evaluate the effect of increased Aβ level on primary cilia, we assessed ciliary dynamics in hippocampal neurons in an APP knock-in AD model (AppNL-G-Fmice) compared to that in wild-type mice. Neuronal cilia length in the CA1, CA3, and dentate gyrus (DG) of wild-type mice increased significantly with age. InAppNL-G-Fmice, such elongation was detected in the DG but not in the CA1 and CA3, where more Aβ accumulation was observed. We further demonstrated that Aβ1-42 treatment decreased cilia length both in hTERT-RPE1 cells and dissociated rat hippocampal neurons. There is growing evidence that reduced cilia length is associated with perturbations of synaptic connectivity and dendrite complexity. Thus, our observations raise the important possibility that structural alterations in neuronal cilia might have a role in AD development.