Experimental neurology · 2025
Low-density lipoprotein receptor interacts with clusterin to regulate A1/A2 astrocyte polarization and ameliorate hemorrhagic brain injury.
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Yin Hongwei, Li Xiang, Yang Jian, Lu Jinxin, Xu Zhongmou, Bai Lei, Liu Jianmin, Sun Chunming, Li Haiying
Аннотация
BACKGROUND: Intracerebral hemorrhage (ICH) has high mortality and disability rates. Astrocytes polarize into neurotoxic A1 or neuroprotective A2 subtypes. The low-density lipoprotein receptor (LDLR) improves outcomes in neurodegenerative diseases, Single-cell sequencing analysis identifies differential Ldlr expression among subtype astrocyte post-intracerebral hemorrhage, exhibiting strong correlation with astrocyte activation. This study explores how LDLR influences astrocyte polarization and its underlying mechanism.
METHODS: Single-cell sequencing analysis assessed Ldlr expression in astrocytes and its correlation with polarization. ICH model was established in C57BL/6 J mice through stereotactic injection of autologous blood. A1 (C3+) and A2 (S100A10+) astrocytes were labeled to monitor polarization. Astrocyte-targeted adeno-associated virus (AAVs) transfection generated Ldlr knockdown mice, and mass spectrometry elucidated LDLR's molecular mechanism in astrocyte polarization and brain injury.
RESULTS: Single-cell sequencing analysis showed upregulated Ldlr in astrocyte subpopulations, linked to activation. Further experiments have shown LDLR expression increased post-ICH, peaking on day 3, and co-localized with astrocytes. Ldlr knockdown promoted A1 polarization and worsened brain injury. Mass spectrometry and co-immunoprecipitation revealed that Clusterin (CLU) is an important interacting protein. Exogenous CLU enhanced A2 polarization and improved outcomes, but this effect was abolished in Ldlr knockdown mice.
CONCLUSION: LDLR interacts with CLU post-ICH to shift astrocytes from A1 to A2, mitigating brain injury. Targeting LDLR and CLU may offer therapeutic potential for hemorrhagic brain injury.
METHODS: Single-cell sequencing analysis assessed Ldlr expression in astrocytes and its correlation with polarization. ICH model was established in C57BL/6 J mice through stereotactic injection of autologous blood. A1 (C3+) and A2 (S100A10+) astrocytes were labeled to monitor polarization. Astrocyte-targeted adeno-associated virus (AAVs) transfection generated Ldlr knockdown mice, and mass spectrometry elucidated LDLR's molecular mechanism in astrocyte polarization and brain injury.
RESULTS: Single-cell sequencing analysis showed upregulated Ldlr in astrocyte subpopulations, linked to activation. Further experiments have shown LDLR expression increased post-ICH, peaking on day 3, and co-localized with astrocytes. Ldlr knockdown promoted A1 polarization and worsened brain injury. Mass spectrometry and co-immunoprecipitation revealed that Clusterin (CLU) is an important interacting protein. Exogenous CLU enhanced A2 polarization and improved outcomes, but this effect was abolished in Ldlr knockdown mice.
CONCLUSION: LDLR interacts with CLU post-ICH to shift astrocytes from A1 to A2, mitigating brain injury. Targeting LDLR and CLU may offer therapeutic potential for hemorrhagic brain injury.