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Endothelial LRP1 clears proteinaceous toxins at the blood\u2013brain barrier (BBB), regulates angiogenesis, and is increasingly reduced in Alzheimer\u2019s 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\u2013matrix 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.<\/jats:p>","DOI":"10.1084\/jem.20202207","type":"journal-article","created":{"date-parts":[[2021,2,6]],"date-time":"2021-02-06T05:16:14Z","timestamp":1612588574000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":120,"title":["Endothelial LRP1 protects against neurodegeneration by blocking cyclophilin A"],"prefix":"10.1084","volume":"218","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1621-4965","authenticated-orcid":true,"given":"Angeliki Maria","family":"Nikolakopoulou","sequence":"first","affiliation":[{"name":"Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, Los Angeles, CA 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