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 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 10

Deletion of Lrp1 in brain endothelial cells leads to cognitive deficits in 5xFAD Lrp1BE–/– mice.

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Deletion of Lrp1 in brain endothelial cells leads to cognitive deficits ...
7-month-old female 5xFAD Lrp1BE–/– (n = 5), 5xFAD Lrp1BEfl/fl (n = 7), Lrp1BE–/– (n = 5), and WT (n = 6) control mice were tested. (A) Animals underwent acquisition training to learn to use proximal and distal cues to navigate a path to a hidden platform. A significant difference in the escape latency of 5xFAD Lrp1BE–/– mice compared with that of all other groups was seen on days 3 to 5. (B and E) Swimming speed was not affected in all mice tested. (C) Spatial reference memory deficits in 5xFAD Lrp1BE–/– mice were shown in the probe trial, in which 5xFAD Lrp1BE–/– mice spent significantly less time in the target quadrant than all other groups of mice. The probe trial was given after the acquisition training phase to assess spatial reference memory. (D) 5xFAD Lrp1BEfl/fl mice showed no impairment of spatial reference memory, as reflected by the significant greater percentage of time spent in the target quadrant (P < 0.001 target vs. left, right, and opposite quadrant). The probe trial revealed a significant impairment of spatial reference memory in 5xFAD Lrp1BE–/– mice, as they showed no preference for the target quadrant. T, target quadrant; L, left quadrant; R, right quadrant; O, opposite quadrant. Data represent mean ± SEM. For statistical analyses, the following test was used: repeated-measures ANOVA followed by Bonferroni multiple comparisons. *P < 0.05, ***P < 0.001.