Suppressing APOE4-induced neural pathologies by targeting the VHL-HIF axis

• 成果类型: Article
• 署名作者: Jiang, Wei I.; Cao, Yiming; Xue, Yue; Ji, Yichun; Winer, Benjamin Y.; Chandra, Rashmi; Zhang, Xingyuan Fischer; Zhang, Mengqi; Singhal, Neel S.; Pierce, Jonathan T.; Chen, Song; Ma, Dengke K.
• 署名单位: University of California System; University of California Berkeley; University of California San Francisco; China Pharmaceutical University; Memorial Sloan Kettering Cancer Center; Howard Hughes Medical Institute; University of California System; University of California San Francisco; University of Texas System; University of Texas Austin; University of California System; University of California San Francisco; University of California System; University of California Berkeley
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-10379
• DOI: 10.1073/pnas.2417515122
• 发表日期: 2025-02-04
• 关键词: caenorhabditis-elegans; macular degeneration; apolipoprotein-e; type-4 allele; cholesterol; apoe; association; resistance; longevity; genetics

摘要

The 84 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 and propose that targeting this pathway in nonproliferative tissues may curb cellular damage, protect against neurodegeneration, and reduce tissue injuries and mortality.