Cell-specific Nav1.6 knockdown reduced astrocyte-derived Aβ by reverse Na+-Ca2+ transporter-mediated autophagy in alzheimer-like mice,Journal of Advanced Research

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Cell-specific Nav1.6 knockdown reduced astrocyte-derived Aβ by reverse Na+-Ca2+ transporter-mediated autophagy in alzheimer-like mice
Journal of Advanced Research ( IF 11.4 ) Pub Date : 2024-07-28 , DOI: 10.1016/j.jare.2024.07.024
Xin Wang ₁ , Wei Wu ₁ , Guang Yang ₂ , Xue-Wei Yang ₁ , Xu Ma ₁ , Dan-Dan Zhu ₁ , Kabir Ahmad ₁ , Khizar Khan ₁ , Ying-Zi Wang ₁ , Ao-Ran Sui ₁ , Song-Yu Guo ₁ , Yue Kong ₁ , Bo Yuan ₁ , Tian-Yuan Luo ₁ , Cheng-Kang Liu ₁ , Peng Zhang ₁ , Yue Zhang ₁ , Qi-Fa Li ₁ , Bin Wang ₁ , Qiong Wu ₁ , Xue-Fei Wu ₁ , Zhi-Cheng Xiao ₃ , Quan-Hong Ma ₄ , Shao Li ₁

Affiliation

Introduction

Nav1.6 is closely related to the pathology of Alzheimer’s Disease (AD), and astrocytes have recently been identified as a significant source of β-amyloid (Aβ). However, little is known about the connection between Nav1.6 and astrocyte-derived Aβ.

Objective

This study explored the crucial role of Nav1.6 in mediated astrocyte-derived Aβ in AD and knockdown astrocytic Nav1.6 alleviates AD progression by promoting autophagy and lysosome-APP fusion.

Methods

A mouse model for astrocytic Nav1.6 knockdown was constructed to study the effects of astrocytic Nav1.6 on amyloidosis. The role of astrocytic Nav1.6 on autophagy and lysosome-APP(amyloid precursor protein) fusion was used by transmission electron microscope, immunostaining, western blot and patch clamp. Glial cell activation was detected using immunostaining. Neuroplasticity and neural network were assessed using patch-clamp, Golgi stain and EEG recording. Behavioral experiments were performed to evaluate cognitive defects.

Results

Astrocytic Nav1.6 knockdown reduces amyloidosis, alleviates glial cell activation and morphological complexity, improves neuroplasticity and abnormal neural networks, as well as promotes learning and memory abilities in APP/PS1 mice. Astrocytic Nav1.6 knockdown reduces itself-derived Aβ by promoting lysosome- APP fusion, which is related to attenuating reverse Na⁺-Ca²⁺ exchange current thus reducing intracellular Ca²⁺ to facilitate autophagic through AKT/mTOR/ULK pathway.

Conclusion

Our findings unveil the crucial role of astrocyte-specific Nav1.6 in reducing astrocyte-derived Aβ, highlighting its potential as a cell-specific target for modulating AD progression.

中文翻译：

细胞特异性 Nav1.6 敲除通过反向 Na+-Ca2 + 转运蛋白介导的阿尔茨海默病样小鼠自噬降低星形胶质细胞衍生的 Aβ

介绍

Nav1.6 与阿尔茨海默病（AD）的病理学密切相关，星形胶质细胞最近被确定为 β-淀粉样蛋白（Aβ）的重要来源。然而，人们对 Nav1.6 与星形胶质细胞衍生的 Aβ 之间的联系知之甚少。

目的

本研究探讨了 Nav1.6 在介导的星形胶质细胞衍生的 Aβ 中的关键作用，敲除星形胶质细胞 Nav1.6 通过促进自噬和溶酶体-APP 融合来缓解 AD 进展。

方法

构建星形胶质细胞 Nav1.6 敲低小鼠模型，研究星形胶质细胞 Nav1.6 对淀粉样变性的影响。通过透射电子显微镜、免疫染色、western blot 和膜片钳分析星形胶质细胞 Nav1.6 对自噬和溶酶体-APP （淀粉样蛋白前体蛋白）融合的作用。使用免疫染色检测神经胶质细胞活化。使用膜片钳、高尔基染色和 EEG 记录评估神经可塑性和神经网络。进行行为实验以评估认知缺陷。

结果

星形胶质细胞 Nav1.6 敲低可减少淀粉样变性，减轻神经胶质细胞活化和形态复杂性，改善神经可塑性和异常神经网络，并促进 APP/PS1 小鼠的学习和记忆能力。星形胶质细胞 Nav1.6 敲除通过促进溶酶体-APP 融合来降低自身衍生的 Aβ，这与减弱反向 Na⁺-Ca²⁺ 交换电流有关，从而减少细胞内 Ca²⁺ 以促进通过 AKT/mTOR/ULK 通路自噬。