HIF1 Stabilization by Roxadustat Improves Cognition and Prevents Neuron Loss in Alzheimer's Diseases In Vivo

Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorders worldwide and is characterized by progressive memory impairment, cognitive decline, and behavioral dysfunction. The brain's high energy demand makes it vulnerable to hypoxia, which can trigger AD pathology. Hypoxia-inducible factor (HIF) is a transcription factor that mediates cellular and tissue adaptation to low oxygen levels. HIF-1 plays a dual role in AD: on the one hand, it is considered a potential neuroprotective target; on the other hand, its activation may exacerbate disease pathogenesis by promoting amyloid plaque formation. Given this ambiguity, further studies are needed. This study investigated the HIF prolyl hydroxylase inhibitor Roxadustat in 6-month-old male 5xFAD mice. Stabilization of the HIF-1 complex exerted a positive effect on learning ability and the retention of long-term spatial memory in 6-month-old male 5xFAD mice. Four-week treatment with Roxadustat significantly reduced pathological morphological alterations in cells of the prefrontal cortex. In addition, animals treated with Roxadustat exhibited significantly increased expression of the brain-derived neurotrophic factor (BDNF) in the cerebral cortex. Our findings suggest that stabilization of the HIF-1 complex through inhibition of HIF prolyl hydroxylase may represent a promising strategy for neuroprotection in AD.