(A–C) LRP1 immunoblotting (#92544 mAb Abcam A), Lrp1 mRNA quantitative real-time PCR (B), and relative Lrp1 mRNA gene expression normalized to Gapdh (housekeeping gene C) in brain endothelial cells cultured from Lrp1 lox/lox littermate control mice (control), Lrp1 lox/+ Tie2-Cre (lox/+) and Lrp1 lox/lox Tie2-Cre (lox/lox) mice. Thus, endothelial LRP1 protects against neurodegeneration by inhibiting cyclophilin A, which has implications for the pathophysiology and treatment of neurodegeneration linked to vascular dysfunction.Įndothelial LRP1 expression and deletion in mice. Cyclophilin A inhibition in mice with endothelial-specific LRP1 knockout restored BBB integrity and reversed and prevented neuronal loss and behavioral deficits. LRP1 endothelial knockout led to a self-autonomous activation of the cyclophilin A-matrix metalloproteinase-9 pathway in the endothelium, causing loss of tight junctions underlying structural BBB impairment. Here, we show that LRP1 inactivation from the mouse endothelium results in progressive BBB breakdown, followed by neuron loss and cognitive deficits, which is reversible by endothelial-specific LRP1 gene therapy. Whether loss of endothelial LRP1 plays a direct causative role in BBB breakdown and neurodegenerative changes remains elusive. Endothelial LRP1 clears proteinaceous toxins at the blood-brain barrier (BBB), regulates angiogenesis, and is increasingly reduced in Alzheimer's disease associated with BBB breakdown and neurodegeneration.

The low-density lipoprotein receptor-related protein 1 (LRP1) is an endocytic and cell signaling transmembrane protein.

Progressive knockout