Endothelial LRP1 transports amyloid- beta sub( 1-42) across the blood-brain barrier

• Published in: The Journal of clinical investigation 2016-01, Vol.126 (1), p.123-123
• Main Authors: Storck, Steffen E, Meister, Sabrina, Nahrath, Julius, Meisner, Julius N, Schubert, Nils, Di Spiezio, Alessandro, Baches, Sandra, Vandenbroucke, Roosmarijn E, Bouter, Yvonne, Prikulis, Ingrid, Korth, Carsten, Weggen, Sascha, Heimann, Axel, Schwaninger, Markus, Bayer, Thomas A, Pietrzik, Claus U
• Format: Article
• Language: English
• ISSN: 0021-9738
• DOI: 10.1172/JCI81108

According to the neurovascular hypothesis, impairment of low-density lipoprotein receptor-related protein-1 (LRP1) in brain capillaries of the blood-brain barrier (BBB) contributes to neurotoxic amyloid- beta (A beta ) brain accumulation and drives Alzheimer's disease (AD) pathology. However, due to conflicting reports on the involvement of LRP1 in A beta transport and the expression of LRP1 in brain endothelium, the role of LRP1 at the BBB is uncertain. As global Lrp1 deletion in mice is lethal, appropriate models to study the function of LRP1 are lacking. In this paper, the authors developed transgenic mouse strains that allow for tamoxifen-inducible deletion of Lrp1 specifically within brain endothelial cells and used these mice to accurately evaluate LRP1-mediated A beta BBB clearance in vivo. Selective deletion of Lrp1 in the brain endothelium of C57BL/6 mice strongly reduced brain efflux of injected A beta sub( 1-42). Together, the results suggest that receptor-mediated A beta BBB clearance may be a potential target for treatment and prevention of A beta brain accumulation in AD.