The largest isoform of Ankyrin-G is required for lattice structure of the axon initial segment
The largest isoform of Ankyrin-G is required for lattice structure of the axon initial segment
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轴突初始段的晶格结构需要最大的 Ankyrin-G 同工型
DOI：
10.1016/j.bbrc.2021.09.017
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发表时间：
2021-09-15
影响因子：
3.1
通讯作者：
Zhang，Yan
中科院分区：
文献类型：
--
作者：
Wang，Yiming;Guan，Meiling;Zhang，Yan
阿尔茨海默病（Alzheimer's disease，AD）是最常见的神经退行性疾病，也是老年人常见的痴呆症。以往的研究发现，轴突起始段（AIS）缺陷与AD之间存在很强的相关性，但AD本身是否改变AIS组分的排列仍不清楚，并且AD中AIS中的衔接蛋白和离子通道受到干扰的机制还不清楚。利用超分辨率结构照明显微镜（SIM）揭示轴突结构，在这里，我们成像了APP/PS1神经元中完全组装的AIS的晶格结构。通过高斯拟合和一维平均自相关分析，我们发现AD模型APP/PS1小鼠中由于480-kDa AnkG的低表达，AnkG，Nav 1. 2和β IV-spectrin的双间距（约200 nm和约370 nm）。为了鉴定每种AnkG同种型的作用，在来自AnkG条件性敲除小鼠的神经元中分别表达两种同种型。用270-kDa AnkG拯救的小鼠在培养的神经元中显示出AnkG组分的双重间距，并且空间记忆受损，而表达480-kDa AnkG的转基因小鼠在AIS中显示出正常的分子分布和正常的认知表现。我们的研究结果为与神经退行性疾病（如AD）相关的认知受损机制提供了新的见解。
Alzheimer's disease (AD) is the most frequent neurodegenerative disease and a common dementia in elderly individuals. Previous studies found a strong correlation between axon initial segment (AIS) defects and AD, but it remains unclear whether AD itself changes the arrangement of AIS components, and the mechanisms by which adaptor proteins and ion channels in the AIS are disturbed in AD are not well understood. With super-resolution structured illumination microscopy (SIM) revealing axonal structures, here we imaged the lattice structure of completely assembled AIS in APP/PS1 neurons. By analyzing the images with Gaussian fitting and 1D mean autocorrelation, we found dual spacings (∼200 nm and ∼370 nm) of Ankyrin-G (AnkG), Nav1.2 and βIV-spectrin in AD model APP/PS1 mice due to the low-expressed 480-kDa AnkG. To identify the roles of each AnkG isoform, two isoforms were separately expressed in neurons from AnkG conditional knockout mice. Mice rescued with 270-kDa AnkG displayed dual spacings of AnkG components in cultured neurons and impaired in spatial memory, while transgenic mice expressing 480-kDa AnkG showed a normal molecular distribution in the AIS and normal cognitive performance. Our findings provide new insight into the mechanisms underlying impaired cognition associated with neurodegenerative diseases such as AD.