PLoS Biology (Sep 2021)

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

  • Virginie Lam,
  • Ryusuke Takechi,
  • Mark J Hackett,
  • Roslyn Francis,
  • Michael Bynevelt,
  • Liesl M Celliers,
  • Michael Nesbit,
  • Somayra Mamsa,
  • Frank Arfuso,
  • Sukanya Das,
  • Frank Koentgen,
  • Maree Hagan,
  • Lincoln Codd,
  • Kirsty Richardson,
  • Brenton O'Mara,
  • Rainer K Scharli,
  • Laurence Morandeau,
  • Jonathan Gauntlett,
  • Christopher Leatherday,
  • Jan Boucek,
  • John C L Mamo

DOI
https://doi.org/10.1371/journal.pbio.3001358
Journal volume & issue
Vol. 19, no. 9
p. e3001358

Abstract

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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.