Endothelial LRP1 transports amyloid-β1–42 across the blood-brain barrier
Steffen E. Storck, … , Thomas A. Bayer, Claus U. Pietrzik
Steffen E. Storck, … , Thomas A. Bayer, Claus U. Pietrzik
Published January 4, 2016; First published November 30, 2015
Citation Information: J Clin Invest. 2016;126(1):123-136. https://doi.org/10.1172/JCI81108.
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Research Article Neuroscience

Endothelial LRP1 transports amyloid-β1–42 across the blood-brain barrier

Abstract

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-β (Aβ) brain accumulation and drives Alzheimer’s disease (AD) pathology. However, due to conflicting reports on the involvement of LRP1 in Aβ 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 Aβ 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 Aβ BBB clearance in vivo. Selective deletion of Lrp1 in the brain endothelium of C57BL/6 mice strongly reduced brain efflux of injected [125I] Aβ1–42. Additionally, in the 5xFAD mouse model of AD, brain endothelial–specific Lrp1 deletion reduced plasma Aβ levels and elevated soluble brain Aβ, leading to aggravated spatial learning and memory deficits, thus emphasizing the importance of systemic Aβ elimination via the BBB. Together, our results suggest that receptor-mediated Aβ BBB clearance may be a potential target for treatment and prevention of Aβ brain accumulation in AD.

Authors

Steffen E. Storck, Sabrina Meister, Julius Nahrath, Julius N. Meißner, Nils Schubert, Alessandro Di Spiezio, Sandra Baches, Roosmarijn E. Vandenbroucke, Yvonne Bouter, Ingrid Prikulis, Carsten Korth, Sascha Weggen, Axel Heimann, Markus Schwaninger, Thomas A. Bayer, Claus U. Pietrzik

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Figure 7

BBB clearance of Aβ species in 5xFAD mice is regulated by brain endothelial LRP1.

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BBB clearance of Aβ species in 5xFAD mice is regulated by brain endothel...
Representative immunoprecipitations of (A) plasma Aβ, (B) soluble brain Aβ, and (C) insoluble brain Aβ, with 6E10 antibody from 7-month-old female mice show impaired brain-to-blood clearance of Aβ1–40 and Aβ1–42. Quantification of (D) plasma Aβ1–40, (E) plasma Aβ1–42, (F) soluble brain Aβ1–40, (G) soluble brain Aβ1–42, (H) insoluble brain Aβ1–40, and (I) insoluble brain Aβ1–42. n = 3 (D and E); n = 4 (F and G); n = 5 (fl/fl) and n = 3 (–/–) (H and I). (J and K) No effect on plaque deposition in hippocampus. n = 5 (fl/fl) and n = 7 (–/–) (K). Quantification of Aβx–40 and Aβx–42 using ELISA showed (L) insoluble and (M) significantly elevated soluble Aβx–40 and Aβx–42 levels in 7-month-old 5xFAD Lrp1BE–/– mice. n = 12, n = 5, n = 12, n = 5 (L) and n = 10, n = 5, n = 12, n = 5 (M) from left to right. Data represent mean ± SEM of n = 5. All samples except for those shown in lanes 1 and 2 in C were analyzed on the same Western blot but rearranged for clearer presentation. A shorter exposure is shown for Aβ1–40 and Aβ1–42 standards in A. For statistical analyses, unpaired t test was used. *P < 0.05, **P < 0.01, ***P < 0.001. Scale bar: 200 μm.