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.
Endothelial LRP1 protects against neurodegeneration by blocking cyclophilin A
Disclosures: J. Körbelin reported personal fees from Boehringer Ingelheim Pharma outside the submitted work; in addition, J. Körbelin had a patent number 10696717 issued and a patent to 10688151 issued. J. Herz reported a patent to 7192714 issued and a patent to 7056688 issued. No other disclosures were reported.
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Angeliki Maria Nikolakopoulou, Yaoming Wang, Qingyi Ma, Abhay P. Sagare, Axel Montagne, Mikko T. Huuskonen, Sanket V. Rege, Kassandra Kisler, Zhonghua Dai, Jakob Körbelin, Joachim Herz, Zhen Zhao, Berislav V. Zlokovic; Endothelial LRP1 protects against neurodegeneration by blocking cyclophilin A. J Exp Med 5 April 2021; 218 (4): e20202207. doi: https://doi.org/10.1084/jem.20202207
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