The involvement of HIF-1α–dependent paracrine factors in Alzheimer’s disease

Activated HIF-1α is a key regulator of various paracrine factors that influence vascular tone, angiogenesis, and cell survival, including endothelin-1, VEGF, Ang-2, erythropoietin, and SDF-1/CXCL12. These factors not only play established roles in vascular biology but are also critical in modulating neurogenesis. The intricate relationship between the brain's vascular system and its neurogenic niches underscores the importance of HIF-1 in facilitating their interactions. Angiogenesis and proper vessel perfusion are vital for the maintenance and proliferation of neural progenitor cells, especially in the context of neurodegenerative diseases such as Alzheimer's disease (AD). In AD, impaired angiogenesis can negatively impact neurogenesis, exacerbating cognitive decline. Recent transcriptomic and proteomic studies have revealed significant upregulation of HIF-1α expression in AD patients, indicating its potential involvement in the pathophysiology of this disease. This review aims to elucidate the role of HIF-1α and related hypoxia-inducible factors in AD, focusing on their diagnostic and therapeutic implications. We specifically examine two critical neurogenic niches in the adult brain: the subventricular zone (SVZ) and the subgranular zone (SGZ). Understanding how HIF-1α affects neurogenesis in these regions may offer novel insights into potential therapeutic strategies for AD, highlighting the need for further research into the intersection of hypoxia, angiogenesis, and neurogenesis in the context of neurodegeneration. By exploring these connections, we hope to contribute to a better understanding of AD pathophysiology and identify new avenues for intervention.