Endothelial LRP1 protects against neurodegeneration by blocking cyclophilin A
Authors
Angeliki Maria Nikolakopoulou, Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, Los Angeles, CA.
Yaoming Wang, Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, Los Angeles, CA.
Qingyi Ma, Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, Los Angeles, CA.
Abhay P. Sagare, Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, Los Angeles, CA.
Axel Montagne, Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, Los Angeles, CA.
Mikko T. Huuskonen, Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, Los Angeles, CA.
Sanket V. Rege, Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, Los Angeles, CA.
Kassandra Kisler, Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, Los Angeles, CA.
Zhonghua Dai, Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, Los Angeles, CA.
Jakob Körbelin, Hubertus Wald Cancer Center, Department of Oncology and Hematology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Joachim Herz, Departments of Neuroscience, Molecular Genetics, and Neurology, University of Texas Southwestern Medical Center, Dallas, TX.
Zhen Zhao, Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, Los Angeles, CA.
Berislav V. Zlokovic, Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, Los Angeles, CA.
Publication Date
4-5-2021
Publication Title
The Journal of experimental medicine
Abstract
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.
Recommended Citation
Nikolakopoulou, Angeliki Maria; Wang, Yaoming; Ma, Qingyi; Sagare, Abhay P.; Montagne, Axel; Huuskonen, Mikko T.; Rege, Sanket V.; Kisler, Kassandra; Dai, Zhonghua; Körbelin, Jakob; Herz, Joachim; Zhao, Zhen; and Zlokovic, Berislav V., "Endothelial LRP1 protects against neurodegeneration by blocking cyclophilin A" (2021). Loma Linda University Faculty Publications. 352.
https://scholarsrepository.llu.edu/fac_pubs/352
