ORP6 regulates astrocytic cholesterol metabolism and brain Aβ deposition

The mammalian brain is the most cholesterol-rich organ of the body, requiring in situ de novo cholesterol synthesis to meet this demand. Defects in brain cholesterol homeostasis are implicated in cognitive deficits related to aging and in neurodegenerative diseases, such as Alzheimer’s Disease (AD). Oxysterol-binding protein (OSBP)-related proteins (ORPs) are highly conserved cytosolic proteins that coordinate lipid homeostasis by regulating cell signaling, inter-organelle membrane contact sites and non-vesicular transport of cholesterol. Here, we show that ORP6 is highly expressed in the brain, where it exhibits spatial and cell-type specific expression. ORP6 expression is enriched in the hippocampus and caudal-putamen brain regions, specifically within neurons and astrocytes. ORP6 knockdown in astrocytes altered the expression of cholesterol biosynthesis, cholesterol efflux and cholesterol esterification genes, resulting in the accumulation of esterified cholesterol within cellular lipid droplets and reduced cholesterol efflux. Furthermore, ORP6 ablation in mice resulted in dysregulation of whole body lipid homeostasis, increased brain desmosterol and Aβ deposition, and cognitive impairment. Our findings highlight a critical role for ORP6 in brain cholesterol homeostasis and identify ORP6 as a potential novel target for the treatment of AD.