Microglial cholesterol reprogramming drives cognitive impairment under hypobaric hypoxia

High-altitude cognitive impairment (HACI) is an irreversible neurological disorder with limited treatment options. Dysregulation of cholesterol homeostasis is an established mechanism of cognitive impairment. However, whether cholesterol dysregulation is involved in HACI remains unknown. This study aims to investigate the role of cholesterol in HACI pathogenesis and elucidate the molecular mechanisms through which high-altitude hypoxia disrupts cholesterol homeostasis. Mice were exposed to hypobaric hypoxia (HH, 7000 m) followed by recovery assays. Cholesterol levels and cognitive function were monitored over time. Microglial depletion (PLX5622), RNA-seq/ATAC-seq, JASPAR analysis, Cut&Tag, and microglia-specific NRF1 knockout were used to dissect molecular pathways. HH exposure in mice induced intracranial cholesterol accumulation, which preceded cognitive decline. Microglial depletion abolished HH-induced intracranial cholesterol accumulation. Multi-omics analyses revealed that hypoxia triggers NRF1-mediated transcriptional activation of HSP90 subunits (Hsp90aa1/Hsp90ab1), leading to SREBP2 nuclear translocation and subsequent activation of cholesterol synthesis. Notably, microglia-specific NRF1 knockout reversed these pathological changes, normalizing cholesterol levels, preventing synaptic loss, and preserving cognitive function under HH. HH exposure upregulates NRF1 in microglia, which induces HSP90 expression and activates the SREBP2-mediated cholesterol synthesis. This cascade promotes pro-inflammatory microglial activation and synaptic pruning, culminating in cognitive impairment. Targeting NRF1 represents a potential therapeutic strategy for HACI.