| First Author | Storck SE | Year | 2016 |
| Journal | J Clin Invest | Volume | 126 |
| Issue | 1 | Pages | 123-36 |
| PubMed ID | 26619118 | Mgi Jnum | J:229820 |
| Mgi Id | MGI:5754651 | Doi | 10.1172/JCI81108 |
| Citation | Storck SE, et al. (2016) Endothelial LRP1 transports amyloid-beta1-42 across the blood-brain barrier. J Clin Invest 126(1):123-36 |
| abstractText | 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 (Abeta) brain accumulation and drives Alzheimer's disease (AD) pathology. However, due to conflicting reports on the involvement of LRP1 in Abeta 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. Moreover, the relevance of systemic Abeta clearance to AD pathology remains unclear, as no BBB-specific knockout models have been available. Here, we developed transgenic mouse strains that allow for tamoxifen-inducible deletion of Lrp1 specifically within brain endothelial cells (Slco1c1-CreERT2 Lrp1fl/fl mice) and used these mice to accurately evaluate LRP1-mediated Abeta BBB clearance in vivo. Selective deletion of Lrp1 in the brain endothelium of C57BL/6 mice strongly reduced brain efflux of injected [125I] Abeta1-42. Additionally, in the 5xFAD mouse model of AD, brain endothelial-specific Lrp1 deletion reduced plasma Abeta levels and elevated soluble brain Abeta, leading to aggravated spatial learning and memory deficits, thus emphasizing the importance of systemic Abeta elimination via the BBB. Together, our results suggest that receptor-mediated Abeta BBB clearance may be a potential target for treatment and prevention of Abeta brain accumulation in AD. |
