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Cited by 35Alzheimer's disease research and treatmentsBarrier Structure and Function StudiesNeuroinflammation and Neurodegeneration Mechanisms

Modeling cerebrovascular pathophysiology in amyloid-β metabolism using neural-crest-derived smooth muscle cells

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Cheung, Christine, Goh, Yeek Teck, Zhang, Jingxian, Wu, Chenghan, Guccione, Ernesto·2014·Cell Reports
DOI 10.1016/j.celrep.2014.08.065
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Abstract

There is growing recognition of cerebrovascular contributions to neurodegenerative diseases. In the walls of cerebral arteries, amyloid-beta (Aβ) accumulation is evident in a majority of aged people and patients with cerebral amyloid angiopathy. Here, we leverage human pluripotent stem cells to generate vascular smooth muscle cells (SMCs) from neural crest progenitors, recapitulating brain-vasculature-specific attributes of Aβ metabolism. We confirm that the lipoprotein receptor, LRP1, functions in our neural-crest-derived SMCs to mediate Aβ uptake and intracellular lysosomal degradation. Hypoxia significantly compromises the contribution of SMCs to Aβ clearance by suppressing LRP1 expression. This enabled us to develop an assay of Aβ uptake by using the neural crest-derived SMCs with hypoxia as a stress paradigm. We then tested several vascular protective compounds in a high-throughput format, demonstrating the value of stem-cell-based phenotypic screening for novel therapeutics and drug repurposing, aimed at alleviating amyloid burden.

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  • Statins (atorvastatin, simvastatin, rosuvastatin, fluvastatin) and ezetimibe were suggested as viable AD repurposing candidates by other studies.

    “Still, statins (atorvastatin, simvastatin, rosuvastatin, fluvastatin) and ezetimibe were suggested as viable AD repurposing candidates by other studies”

    From Drug repurposing for Alzheimer’s disease from 2012–2022—a 10-year literature review (2023) · cites this paper as Cheung et al., 2014

    The Results report that atorvastatin significantly increased amyloid-β uptake in neural-crest-derived smooth muscle cells, and the assay description lists simvastatin among the compounds tested. Our copy does not identify rosuvastatin, fluvastatin, or ezetimibe as Alzheimer’s disease repurposing candidates, nor does it report a beneficial uptake result for simvastatin. No page numbers are available in the indexed passages. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Reported negative outcomes may not entirely discredit the candidacy of certain drugs.

    “suggesting that reported negative outcomes may not entirely discredit the candidacy of certain drugs (Cheung et al., 2014;Croset et al., 2014;Kondo et al., 2017;Bauzon et al., 2020;Wu et al., 2021).”

    From Drug repurposing for Alzheimer’s disease from 2012–2022—a 10-year literature review (2023) · cites this paper as Cheung et al., 2014

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Cited by

Sorted by citations

Authors
Cheung, C., Goh, Y. T., Zhang, J., Wu, C., & Guccione, E.
Affiliations
  • National University of Singapore (SG)
  • Institute of Molecular and Cell Biology (SG)
  • Monash University (AU)
ORCID
Venue
Cell Reports
Publisher
Elsevier BV
Published
2014-10
Volume
9
Issue
1
Pages
391-401
ISSN
2211-1247 (ISSN-L)
DOI
10.1016/j.celrep.2014.08.065
OpenAlex
W2068437368
Cited by
35
References
9
Citations by year
2026: 2 · 2025: 2 · 2024: 3 · 2023: 1 · 2022: 5 · 2021: 3 · 2020: 4 · 2019: 5 · 2018: 3 · 2016: 6 · 2015: 1
FWCI
1.56
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Reports (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Chinese Academy of Agricultural Sciences
  • Institute of Molecular and Cell Biology
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
amyloid-beta metabolism, cerebral amyloid angiopathy, vascular smooth muscle cells, neural crest progenitors, LRP1, amyloid-beta uptake, lysosomal degradation, hypoxia, cerebrovascular pathophysiology, human pluripotent stem cells, high-throughput screening, drug repurposing
MeSH terms
Alzheimer Disease, Animals, Glucose-6-Phosphate Isomerase, HeLa Cells, Humans, Mice, Transgenic, Neural Crest, Amyloid beta-Peptides, Myocytes, Smooth Muscle, Mice

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