Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • 100th Anniversary of Insulin's Discovery (Jan 2021)
    • Hypoxia-inducible factors in disease pathophysiology and therapeutics (Oct 2020)
    • Latency in Infectious Disease (Jul 2020)
    • Immunotherapy in Hematological Cancers (Apr 2020)
    • Big Data's Future in Medicine (Feb 2020)
    • Mechanisms Underlying the Metabolic Syndrome (Oct 2019)
    • Reparative Immunology (Jul 2019)
    • View all review series ...
  • Viewpoint
  • Collections
    • Recently published
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • Recently published
  • In-Press Preview
  • Commentaries
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
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.
View: Text | PDF
Research Article Neuroscience

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

  • Text
  • PDF
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

×

Figure 9

Preferential clearance of Aβ1–40 species by brain endothelial LRP1.

Options: View larger image (or click on image) Download as PowerPoint
Preferential clearance of Aβ1–40 species by brain endothelial LRP1.
Cont...
Contrasting the Aβ1–42/Aβ1–40 ratio in 5xFAD Lrp1BE–/– and 5xFAD Lrp1BEfl/fl Aβ pools demonstrates a differential clearance of Aβ species. Densitometry analysis of immunoprecipitated soluble brain Aβ, insoluble brain Aβ, and plasma Aβ with 6E10 antibody from 7-month-old mice (n = 3, n = 5, n = 7, n = 6, n = 3, n = 3 from left to right) showed higher Aβ1–40 and Aβ1–42/Aβ1–40 ratios in plasma and lower and Aβ1–42/Aβ1–40 ratios in brain fractions when LRP1 is present in brain endothelial cells. Data represent mean ± SEM. For statistical analyses, unpaired t test was used. *P < 0.05, **P < 0.01, ***P < 0.001.
Follow JCI:
Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts