alisporivir and Alzheimer-Disease

The low-density lipoprotein receptor-related protein 1 (LRP1) is an endocytic and cell signaling transmembrane protein. 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. Whether loss of endothelial LRP1 plays a direct causative role in BBB breakdown and neurodegenerative changes remains elusive. 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. 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. Cyclophilin A inhibition in mice with endothelial-specific LRP1 knockout restored BBB integrity and reversed and prevented neuronal loss and behavioral deficits. Thus, endothelial LRP1 protects against neurodegeneration by inhibiting cyclophilin A, which has implications for the pathophysiology and treatment of neurodegeneration linked to vascular dysfunction.

Topics: Alzheimer Disease; Animals; Blood-Brain Barrier; Cells, Cultured; Cognitive Dysfunction; Cyclophilin A; Cyclosporine; Disease Models, Animal; Endothelial Cells; Enzyme Inhibitors; Female; Gene Knockout Techniques; Genetic Therapy; Low Density Lipoprotein Receptor-Related Protein-1; Male; Matrix Metalloproteinase 9; Mice; Mice, Transgenic; Neurons; Signal Transduction

In Alzheimer's disease (AD), the molecular mechanisms involved in the neurodegeneration are still incompletely defined, though this aspect is crucial for a better understanding of the malady and for devising effective therapies. Mitochondrial dysfunctions and altered Ca

Topics: Alzheimer Disease; Animals; Calcium; Cells, Cultured; Cyclosporine; Disease Models, Animal; Electron Transport; Glutamic Acid; Hippocampus; Ions; Membrane Potential, Mitochondrial; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mitochondria; Neurotoxins; Reactive Oxygen Species