Sterol Transport Protein ORP6 Regulates Lipid Metabolism, Amyloid Beta Oligomers (AβOs) Production and Cognition.

Abstract

Cholesterol is an indispensable lipid in the central nervous system (CNS), with more than 25% of the total cholesterol content residing in the brain. Defects in brain cholesterol homeostasis are implicated in neurodegenerative diseases, including Alzheimer’s Disease (AD). Oxysterol-binding protein (OSBP)-related proteins (ORPs) are highly conserved cytosolic lipid transfer proteins that coordinate cholesterol homeostasis by regulating cell signaling, inter-organelle membrane contact sites (MCS), and non-vesicular transport of cholesterol. Within this family of proteins, ORP6, a poorly characterized member, is part of a transcriptional cascade coordinated by the Sterol Regulatory Binding Protein 2 (SREBP2) and Liver X receptor (LXR) and has emerged as a novel regulator of intracellular cholesterol trafficking in hepatocytes and macrophages. Here, we show that ORP6 is highly enriched in the mammalian brain, specifically within neurons and astrocytes, with widespread expression throughout distinct brain regions, including the hippocampus, a region vital for learning and memory. Brain-specific ablation of ORP6 (Osbpl6Δbrain) in mice markedly increased body weight and circulating triglycerides and total cholesterol, with a notable increase in low-density lipoprotein (LDL)-cholesterol. This was accompanied by higher levels of amyloid beta oligomers (AβOs) in the brains of Osbpl6Δbrain mice as compared to Control mice and significant deficits in learning and memory. Together, our findings highlight an unforeseen role for ORP6 in cognition and memory through dysregulation of systemic lipid homeostasis and production of AβOs, thus identifying ORP6 as a potential target for the treatment of AD.