Visualize neuronal membrane cholesterol with split-fluorescent protein tagged YDQA sensor
Yi Xu1, Saixuan Li1, Yiran Xu1
1State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, PR China.
Journal of Lipid Research
|March 21, 2025
Summary
Researchers developed a novel sensor to visualize neuronal cholesterol in vivo. This tool revealed distinct cholesterol changes in Alzheimer's disease models, offering new insights into neurological disorders.
Area of Science:
- Neuroscience
- Biochemistry
- Cell Biology
Background:
- Cholesterol is vital for neuronal plasma membrane (PM) function and brain health.
- Disrupted cholesterol homeostasis is linked to neurological disorders like Alzheimer's disease (AD).
- In vivo visualization of neuronal cholesterol remains a significant challenge in understanding AD pathology.
Purpose of the Study:
- To develop and validate a novel sensor for detecting neuronal PM cholesterol in vivo.
- To investigate cholesterol distribution changes in mouse models of AD.
Main Methods:
- Generation of a split-fluorescent protein-based sensor (sfPMcho) using a cholesterol-dependent cytolysin derivative (YDQA).
- Validation of the sfPMcho sensor in cell and C. elegans models.
- Application of the sfPMcho sensor in 5X FAD and APOE KO mouse models of AD.
Main Results:
- The sfPMcho sensor effectively detects neuronal PM cholesterol in vivo.
- Significant alterations in cholesterol distribution were observed in AD mouse models.
- Specifically, PM cholesterol was sparse and aggregated in neuron bodies but accumulated in nerve fibers.
Conclusions:
- The sfPMcho sensor provides a valuable new tool for in vivo detection of neuronal PM cholesterol.
- This study uncovers specific cholesterol abnormalities at the cellular level in AD-related pathology.
- Further development of such sensors is expected to advance AD research.
