4.6 Article

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

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PLOS BIOLOGY
卷 19, 期 9, 页码 -

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PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pbio.3001358

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  1. National Health and Medical Research Council [GNT1135590, GNT1064567, GNT1156582]
  2. Western Australian Department of Health

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The study showed that in mice engineered to synthesize human Ass only in the liver, there was marked neurodegeneration, capillary dysfunction, parenchymal extravasation of lipoprotein-Ass, and neurovascular inflammation. These findings suggest a potential association between a lipoprotein-Ass/capillary axis and the onset and progression of neurodegenerative diseases.
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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