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

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 gen...

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Published in:PLoS biology 2021-09, Vol.19 (9), p.e3001358-e3001358
Main Authors: Lam, Virginie, Takechi, Ryusuke, Hackett, Mark J., Francis, Roslyn, Bynevelt, Michael, Celliers, Liesl M., Nesbit, Michael, Mamsa, Somayra, Arfuso, Frank, Das, Sukanya, Koentgen, Frank, Hagan, Maree, Codd, Lincoln, Richardson, Kirsty, O’Mara, Brenton, Scharli, Rainer K., Morandeau, Laurence, Gauntlett, Jonathan, Leatherday, Christopher, Boucek, Jan, Mamo, John C. L.
Format: Article
Language:English
Subjects:
Age
Alzheimer's disease
Amyloidosis
Apolipoproteins
Biology and Life Sciences
Engineering and Technology
Extravasation
Fatty acids
Gene expression
Genetic modification
Health risks
Hippocampus
Hypotheses
Lipoproteins
Liver
LSD
Lysergic acid diethylamide
Magnetic resonance imaging
Medicine and Health Sciences
Metabolism
Neurodegeneration
Neurodegenerative diseases
Phenotypes
Plasma
Research and Analysis Methods
Transmission electron microscopy
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Summary: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.
ISSN:1545-7885
1544-9173
1545-7885
DOI:10.1371/journal.pbio.3001358