SOAT1 dysregulation in astrocytes drives Blood-Brain barrier dysfunction and neuroinflammation in Alzheimer's disease

Alzheimer's disease (AD) is a neurodegenerative disorder that leads to memory loss and cognitive decline, in which blood-brain barrier (BBB) and astrocyte dysfunction are significantly involved. Recent evidence suggests that dysregulation of lipid metabolism in astrocytes contributes to BBB disruption and neuroinflammation in AD. Sterol O-acyltransferase 1 (SOAT1), an enzyme involved in Cholesterol esterification, has been implicated in BBB disruption and neuroinflammation, but its specific role in AD remains unclear. This study aimed to investigate the impact of SOAT1 on lipid metabolism, BBB integrity, and neuroinflammation in AD. Using Oil Red O staining of human autopsy brain tissue and reanalysis of publicly available single-nucleus RNA Sequencing (snRNA-seq) data, we identified a significant increase in lipid droplet accumulation and lipid metabolism gene expression, particularly in astrocytes, in the brains of AD patients. Furthermore, in vitro BBB models and the 5 × FAD mouse model were used to explore how SOAT1 expression influences BBB function. Our results demonstrated that elevated SOAT1 expression in astrocytes was positively correlated with increased lipid droplet accumulation and compromised BBB integrity. Knockdown of SOAT1 using siRNA or treatment with the SOAT1 inhibitor K604 restored BBB function, reduced neuroinflammation, and improved cognitive function in 5 × FAD mice. These findings suggest that SOAT1 plays a critical role in astrocytic lipid metabolism and BBB dysfunction in AD. Targeting SOAT1 may be a promising therapeutic approach to alleviate neuroinflammation and restore cognitive function in AD patients.