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

Abstract

The ε4 variant of human apolipoprotein E (<i>APOE4</i>) 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 <i>APOE4</i> 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 <i>APOE4</i> in <i>Caenorhabditis elegans</i>. 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 <i>Vhl</i> reduces cerebral vascular injury and synaptic lesions in <i>APOE4</i> mice, suggesting an evolutionarily conserved mechanism. Thus, we identify the VHL-HIF axis as a potent modulator of <i>APOE4</i>-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.