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Cited by 114Alzheimer's disease research and treatmentsBarrier Structure and Function StudiesNeuroinflammation and Neurodegeneration Mechanisms

LRP1 Has a Predominant Role in Production over Clearance of Aβ in a Mouse Model of Alzheimer’s Disease

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Van Gool, Bart, Storck, Steffen E., Reekmans, Sara M., Lechat, Benoit, Gordts, Philip L. S. M., Pradier, Laurent, Pietrzik, Claus U., Roebroek, Anton J. M.·2019·Molecular Neurobiology
DOI 10.1007/s12035-019-1594-2PMC PMC6728278
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Abstract

The low-density lipoprotein receptor-related protein-1 (LRP1) has a dual role in the metabolism of the amyloid precursor protein (APP). In cellular models, LRP1 enhances amyloid-β (Aβ) generation via APP internalization and thus its amyloidogenic processing. However, conditional knock-out studies in mice define LRP1 as an important mediator for the clearance of extracellular Aβ from brain via cellular degradation or transcytosis across the blood-brain barrier (BBB). In order to analyze the net effect of LRP1 on production and clearance of Aβ in vivo, we crossed mice with impaired LRP1 function with a mouse model of Alzheimer's disease (AD). Analysis of Aβ metabolism showed that, despite reduced Aβ clearance due to LRP1 inactivation in vivo, less Aβ was found in cerebrospinal fluid (CSF) and brain interstitial fluid (ISF). Further analysis of APP metabolism revealed that impairment of LRP1 in vivo shifted APP processing from the Aβ-generating amyloidogenic cleavage by beta-secretase to the non-amyloidogenic processing by alpha-secretase as shown by a decrease in extracellular Aβ and an increase of soluble APP-α (sAPP-α). This shift in APP processing resulted in overall lower Aβ levels and a reduction in plaque burden. Here, we present for the first time clear in vivo evidence that global impairment of LRP1's endocytosis function favors non-amyloidogenic processing of APP due to its reduced internalization and subsequently, reduced amyloidogenic processing. By inactivation of LRP1, the inhibitory effect on Aβ generation overrules the simultaneous impaired Aβ clearance, resulting in less extracellular Aβ and reduced plaque deposition in a mouse model of AD.

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  • In mouse model of AD and AD patients, BBB benefits clearance of Aβ aggregates through efflux of amyloid from brain by dedicated transporters such as LRP1 and P-glycoprotein.

    “In mouse model of AD and AD patients, BBB benefits the clearance of Aβ aggregates through the efflux of amyloid from the brain by dedicated transporters, such as LRP1 (lipoprotein receptor-related protein-1) and P-glycoprotein,136,137”

    From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [136]

    The Introduction says that LRP1 and P-glycoprotein act together in Aβ transcytosis across the BBB, and the Results report reduced brain-to-blood Aβ transport when LRP1 function is impaired in mouse endothelial cells. The paper does not establish this transporter-mediated efflux in AD patients or show that Aβ aggregates, specifically, are transported by this route. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Receptors such as LRP1 can regulate APP endocytosis and amyloidogenic processing while also mediating cellular uptake and clearance of extracellular Aβ.

    “Receptors such as LRP1 can regulate APP endocytosis and amyloidogenic processing while also mediating cellular uptake and clearance of extracellular Aβ (Kanekiyo and Bu, 2014; Kanekiyo et al., 2013; Van Gool et al., 2019).”

    From Isogenic human stem cell models reveal mutation-dependent protective mechanisms of APOE3 Christchurch (2026) · cites this paper as Van Gool et al., 2019

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Cited by

Sorted by citations

Authors
Van Gool, B., Storck, S. E., Reekmans, S. M., Lechat, B., Gordts, P. L. S. M., Pradier, L., Pietrzik, C. U., & Roebroek, A. J. M.
Affiliations
  • Johannes Gutenberg University Mainz (DE)
  • KU Leuven (BE)
  • University of California San Diego (US)
  • Sanofi (France) (FR)
Corresponding author
Roebroek, Anton J. M.
ORCID
Venue
Molecular Neurobiology
Publisher
Springer Science and Business Media LLC
Published
2019-04-19
Volume
56
Issue
10
Pages
7234-7245
ISSN
  • 0893-7648 (ISSN-L)
  • 1559-1182
DOI
10.1007/s12035-019-1594-2
PMC
PMC6728278
OpenAlex
W2939257077
Cited by
114
References
8
Citations by year
2026: 12 · 2025: 22 · 2024: 15 · 2023: 16 · 2022: 11 · 2021: 25 · 2020: 11 · 2019: 1
FWCI
8.23
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Neurobiology (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Lirias (submittedVersion, cc-by)
  • eScholarship (California Digital Library) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
Funders
  • Institute for Innovation through Science and Technology in Flanders (IWT-Vlaanderen)
  • Intramural Funding Program of the University Medical Center of the Johannes Gutenberg University Mainz
  • American Health Assistance Foundation (A2007-096)
  • Foundation Alzheimer Research (ISAO 04602, SAO-FRMA 06601)
  • Deutsche Forschungsgemeinschaft (PA930/12, PI 379/8-1)
  • EU Joint Programme – Neurodegenerative Disease Research (PROP-AD: BMBF #01ED1605 - Germany)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
LRP1, amyloid-beta, Alzheimer's disease, amyloid precursor protein, APP processing, alpha-secretase, beta-secretase, endocytosis, amyloid clearance, blood-brain barrier, cerebrospinal fluid, brain interstitial fluid, amyloid plaques, mouse model
MeSH terms
Alzheimer Disease, Animals, Brain, Disease Models, Animal, Mutation, Amyloid beta-Peptides, Amino Acid Motifs, Low Density Lipoprotein Receptor-Related Protein-1, Endothelial Cells, Mice, Plaque, Amyloid

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