LRP1 mediates bidirectional transcytosis of amyloid-β across the blood-brain barrier
Abstract
According to the "amyloid hypothesis", the amyloid-β (Aβ) peptide is the toxic intermediate driving Alzheimer's disease (AD) pathogenesis. Recent evidence suggests that the low density lipoprotein receptor-related protein 1 (LRP1) transcytoses Aβ out of the brain across the blood-brain barrier (BBB). To provide genetic evidence for LRP1-mediated transcytosis of Aβ across the BBB we analyzed Aβ transcytosis across primary mouse brain capillary endothelial cells (pMBCECs) derived from wild-type and LRP1 knock-in mice. Here, we show that pMBCECs in vitro express functionally active LRP1. Moreover, we demonstrate that LRP1 mediates transcytosis of [(125)I]-Aβ(1-40) across pMBCECs in both directions, whereas no role for LRP1-mediated Aβ degradation was detected. Analysis of [(125)I]-Aβ(1-40) transport across pMBCECs generated from mice harboring a knock-in mutation in the NPxYxxL endocytosis/sorting domain of endogenous LRP1 revealed a reduced Aβ clearance from brain-to-blood and blood-to-brain compared with wild-type derived pMBCECs. Therefore, for the first time, we present genetic evidence that LRP1 modulates the pathogenic actions of soluble Aβ in the brain by clearing Aβ across the BBB.
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Some exchangeable apolipoproteins (ApoA1 and ApoE) can cross the blood-brain barrier via receptor-mediated transcytosis.
“Some of those exchangeable apolipoproteins (ApoA1 and ApoE) can cross the blood-brain barrier (BBB) via receptor-mediated transcytosis18–21”
From Brain-targeted drug delivery by manipulating protein corona functions (2019) · cites this paper as [20]
Cites
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Self-citation
- Authors
- Pflanzner, T., Janko, M. C., André-Dohmen, B., Reuss, S., Weggen, S., Roebroek, A. J. M., Kuhlmann, C. R. W., & Pietrzik, C. U.
- Affiliations
- Johannes Gutenberg University Mainz (DE)
- Heinrich Heine University Düsseldorf (DE)
- KU Leuven (BE)
- Corresponding author
- Pietrzik, Claus U.
- Venue
- Neurobiology of Aging
- Publisher
- Elsevier BV
- Published
- 2011-12
- Volume
- 32
- Issue
- 12
- Pages
- 2323.e1-2323.e11
- ISSN
- 0197-4580 (ISSN-L)
- OpenAlex
- W2034087941
- Cited by
- 141
- References
- 7
- Citations by year
- 2026: 9 · 2025: 10 · 2024: 6 · 2023: 9 · 2022: 9 · 2021: 10 · 2020: 8 · 2019: 6 · 2018: 7 · 2017: 13 · 2016: 6 · 2015: 6 · 2014: 15 · 2013: 9 · 2012: 13
- FWCI
- 5.85
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neurobiology of Aging (publishedVersion)
- PubMed (publishedVersion)
- Funders
- German Federal Ministry of Education and Research (01GI0719)
- Alzheimer's disease Research (A2007-096)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- LRP1, amyloid-beta, blood-brain barrier, transcytosis, Alzheimer's disease, amyloid hypothesis, brain microvascular endothelial cells, amyloid-beta clearance
- MeSH terms
- Animals, Blood-Brain Barrier, Cells, Cultured, Mice, Inbred C57BL, Peptide Fragments, Receptors, LDL, Amyloid beta-Peptides, Tumor Suppressor Proteins, Low Density Lipoprotein Receptor-Related Protein-1, Mice, Gene Knock-In Techniques, Mice, 129 Strain, Transcytosis
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