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Cited by 80Alzheimer's disease research and treatmentsBarrier Structure and Function StudiesNeuroinflammation and Neurodegeneration Mechanisms

Synthesis of human amyloid restricted to liver results in an Alzheimer disease–like neurodegenerative phenotype

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Lam, Virginie, Takechi, Ryusuke, Hackett, Mark J., Francis, Roslyn, Bynevelt, Michael, Celliers, Liesl M., Nesbit, Michael, Mamsa, Somayra +13 more·2021·PLOS Biology
DOI 10.1371/journal.pbio.3001358PMC PMC8439475
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Abstract

Several lines of study suggest that peripheral metabolism of amyloid beta (Aß) is associated with risk for Alzheimer disease (AD). In blood, greater than 90% of Aß is complexed as an apolipoprotein, raising the possibility of a lipoprotein-mediated axis for AD risk. In this study, we report that genetic modification of C57BL/6J mice engineered to synthesise human Aß only in liver (hepatocyte-specific human amyloid (HSHA) strain) has marked neurodegeneration concomitant with capillary dysfunction, parenchymal extravasation of lipoprotein-Aß, and neurovascular inflammation. Moreover, the HSHA mice showed impaired performance in the passive avoidance test, suggesting impairment in hippocampal-dependent learning. Transmission electron microscopy shows marked neurovascular disruption in HSHA mice. This study provides causal evidence of a lipoprotein-Aß /capillary axis for onset and progression of a neurodegenerative process.

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Authors
Lam, V., Takechi, R., Hackett, M. J., Francis, R., Bynevelt, M., Celliers, L. M., Nesbit, M., Mamsa, S., Arfuso, F., Das, S., Koentgen, F., Hagan, M., Codd, L., Richardson, K., O’Mara, B., Scharli, R. K., Morandeau, L., Gauntlett, J., Leatherday, C., Boucek, J., & Mamo, J. C. L.
Affiliations
  • Curtin University (AU)
  • The University of Western Australia (AU)
  • Sir Charles Gairdner Hospital (AU)
  • Fiona Stanley Hospital (AU)
  • East Metropolitan Health Service (AU)
Corresponding author
Mamo, John C. L.
ORCID
Venue
PLOS Biology
Publisher
Public Library of Science (PLoS)
Published
2021-09-14
Volume
19
Issue
9
Pages
e3001358
ISSN
  • 1544-9173 (ISSN-L)
  • 1545-7885
DOI
10.1371/journal.pbio.3001358
PMC
PMC8439475
OpenAlex
W3199655522
Cited by
80
References
8
Citations by year
2026: 10 · 2025: 11 · 2024: 21 · 2023: 14 · 2022: 21 · 2021: 3
FWCI
10.40
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS Biology (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • UWA Profiles and Research Repository (UWA) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Health and Medical Research Council (GNT1135590, GNT1064567, GNT1156582)
  • Department of Health, Government of Western Australia
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
Alzheimer's disease, amyloid-beta, neurovascular dysfunction, capillary dysfunction, neurovascular inflammation, hippocampus-dependent learning, passive avoidance, neurodegeneration, mouse model
MeSH terms
Alzheimer Disease, Animals, Blood-Brain Barrier, Brain, Capillaries, Disease Models, Animal, Humans, Inflammation, Learning, Lipoproteins, Male, Mice, Transgenic, Nerve Degeneration, Amyloid beta-Peptides, Hepatocytes

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