Suppressing APOE4-induced neural pathologies by targeting the VHL–HIF axis Journal Article
| Authors: | Jiang, W. I.; Cao, Y.; Xue, Y.; Ji, Y.; Winer, B. Y.; Chandra, R.; Zhang, X. F.; Zhang, M.; Singhal, N. S.; Pierce, J. T.; Chen, S.; Ma, D. K. |
| Article Title: | Suppressing APOE4-induced neural pathologies by targeting the VHL–HIF axis |
| 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. Copyright © 2025 the Author(s). |
| Keywords: | controlled study; human cell; genetics; mortality; nonhuman; mouse; animal; metabolism; animals; mice; animal tissue; animal experiment; genetic association; transcription factor; immunofluorescence; pathology; risk factor; histology; transgenic mouse; mice, transgenic; transcription factors; hypoxia; tumor suppressor gene; chemotaxis; immunocytochemistry; escherichia coli; western blotting; blood brain barrier; reactive oxygen metabolite; aging; cholesterol; hypoxia inducible factor; real time polymerase chain reaction; upregulation; oxidative stress; anxiety; caenorhabditis elegans; genetic risk; superoxide; mitochondria; transcriptome; mitochondrion; alzheimer disease; von hippel lindau protein; glutathione; cerebrovascular accident; rna sequence; nerve degeneration; neurodegeneration; hippocampus; caenorhabditis elegans protein; caenorhabditis elegans proteins; chromosome 5; protein homeostasis; apolipoprotein e; brain tissue; mitochondrial dysfunction; temperature stress; apolipoprotein e4; mitochondrial biogenesis; von hippel-lindau tumor suppressor protein; mitophagy; humans; human; article; hek293t cell line; all cause mortality; apoe4; vhl–hif axis; hif-1 protein, c elegans; abiotic stress; neural pathology |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 122 |
| Issue: | 5 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2025-02-04 |
| Start Page: | e2417515122 |
| Language: | English |
| DOI: | 10.1073/pnas.2417515122 |
| PUBMED: | 39874294 |
| PROVIDER: | scopus |
| PMCID: | PMC11804744 |
| DOI/URL: | |
| Notes: | Source: Scopus |
