Xu Yi, Li Saixuan, Xu Yiran, Sun Xiaoqin, Wei Yuqing, Wang Yuejun, Li Shuang, Ji Yongqi, Hu Keyi, Xu Yuxia, Zhu Cuiqing, Lu Bin, Wang Dandan
State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, PR China.
State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, PR China.
J Lipid Res. 2025 May;66(5):100781. doi: 10.1016/j.jlr.2025.100781. Epub 2025 Mar 19.
Cholesterol is a major component of the cellular plasma membrane (PM), and its homeostasis is essential for brain health. Dysregulated cholesterol homeostasis has been strongly implicated in the pathogenesis of various neurological disorders, including Alzheimer's disease (AD). However, in vivo visualization of cholesterol has remained challenging, hindering a comprehensive understanding of AD pathology. In this study, we generated a new sensor combining the split-fluorescent protein tags with YDQA, a derivate of cholesterol-dependent cytolysin PFO. Through a series of validations in cell and C. elegans models, we demonstrate that the new sensor (name as sfPMcho) efficiently detects neuronal PM cholesterol. We further applied this sensor in 5X FAD and APOE KO mice models and revealed the cholesterol changes within neurons. PM cholesterol became sparse and locally aggregated in neuron bodies but significantly accumulated in nerve fibers. Collectively, this study provides a new tool for detecting neuronal PM cholesterol in vivo and uncovers cholesterol abnormalities in AD-related pathology at the cellular level. Further development based on this sensor or a similar strategy is to be expected.
胆固醇是细胞质膜（PM）的主要成分，其体内平衡对大脑健康至关重要。胆固醇体内平衡失调与包括阿尔茨海默病（AD）在内的各种神经疾病的发病机制密切相关。然而，胆固醇的体内可视化仍然具有挑战性，这阻碍了对AD病理学的全面理解。在本研究中，我们生成了一种新的传感器，将分裂荧光蛋白标签与胆固醇依赖性细胞溶素PFO的衍生物YDQA相结合。通过在细胞和秀丽隐杆线虫模型中的一系列验证，我们证明了这种新传感器（命名为sfPMcho）能够有效地检测神经元质膜胆固醇。我们进一步将该传感器应用于5XFAD和APOE基因敲除小鼠模型，揭示了神经元内的胆固醇变化。质膜胆固醇在神经元胞体中变得稀疏并局部聚集，但在神经纤维中显著积累。总的来说，本研究提供了一种在体内检测神经元质膜胆固醇的新工具，并在细胞水平上揭示了AD相关病理学中的胆固醇异常。基于该传感器或类似策略的进一步发展值得期待。
