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), Na_v1.2 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.

阿尔茨海默病 (AD) 是最常见的神经退行性疾病，也是老年人常见的痴呆症。先前的研究发现轴突初始节段（AIS）缺陷与AD之间存在很强的相关性，但尚不清楚AD本身是否会改变AIS成分的排列，以及AIS中的衔接蛋白和离子通道在AD中受到干扰的机制尚不清楚非常明白。通过超分辨率结构照明显微镜 (SIM) 揭示轴突结构，我们在这里对 APP/PS1 神经元中完全组装的 AIS 的晶格结构进行了成像。通过使用高斯拟合和一维平均自相关分析图像，我们发现 Ankyrin-G (AnkG)、Na _{v的双间距（~200 nm 和~370 nm）}由于低表达的 480-kDa AnkG，AD 模型 APP/PS1 小鼠中的 1.2 和 βIV-Spectrin。为了确定每种 AnkG 同种型的作用，两种同种型分别在 AnkG 条件性敲除小鼠的神经元中表达。用 270-kDa AnkG 拯救的小鼠在培养的神经元中表现出双间距的 AnkG 成分，并且空间记忆受损，而表达 480-kDa AnkG 的转基因小鼠在 AIS 中表现出正常的分子分布和正常的认知能力。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。