Suppressing APOE4-induced Neural Pathologies by Targeting the VHL-HIF Axis.

Wei I Jiang,Yiming Cao, Yue Xue, Yichun Ji,Benjamin Y Winer,Rashmi Chandra, Xingyuan Fischer Zhang,Mengqi Zhang,Neel S Singhal,Jonathan T Pierce,Song Chen,Dengke K Ma

Proceedings of the National Academy of Sciences of the United States of America（2025）

Cardiovascular Research Institute | Department of Neurology

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Abstract

The ε4 variant of human apolipoprotein E (APOE4) is a key genetic risk factor for neurodegeneration in Alzheimer's disease and elevated all-cause mortality in humans. Understanding the factors and mechanisms that can mitigate the harmful effects of APOE4 has significant implications. In this study, we find that inactivating the VHL-1 (Von Hippel-Lindau) protein can suppress mortality, neural and behavioral pathologies caused by transgenic human APOE4 in Caenorhabditis elegans. The protective effects of VHL-1 deletion are recapitulated by stabilized HIF-1 (hypoxia-inducible factor), a transcription factor degraded by VHL-1. HIF-1 activates a genetic program that safeguards against mitochondrial dysfunction, oxidative stress, proteostasis imbalance, and endolysosomal rupture-critical cellular events linked to neural pathologies and mortality. Furthermore, genetic inhibition of Vhl reduces cerebral vascular injury and synaptic lesions in APOE4 mice, suggesting an evolutionarily conserved mechanism. Thus, we identify the VHL-HIF axis as a potent modulator of APOE4-induced neural pathologies and propose that targeting this pathway in nonproliferative tissues may curb cellular damage, protect against neurodegeneration, and reduce tissue injuries and mortality.

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【要点】：本研究发现通过抑制VHL-HIF轴可以有效减轻APOE4引起的神经退行性病变，提出了一种新的神经保护机制。

【方法】：研究通过在秀丽线虫Caenorhabditis elegans中抑制VHL-1蛋白以及稳定HIF-1转录因子，观察APOE4引起的病理变化。

【实验】：实验在秀丽线虫和APOE4小鼠模型中进行，通过遗传学方法抑制Vhl，观察到了脑血管损伤和突触病变的减少，使用的数据集未明确提及，但实验结果表明VHL-HIF轴在调节APOE4引起的神经病理学中起重要作用。