Open AccessSynthesis of human amyloid restricted to liver results in an Alzheimer disease–like neurodegenerative phenotype
Author(s) -
Virginie Lam,
Ryusuke Takechi,
Mark J. Hackett,
Roslyn J. Francis,
Michael Bynevelt,
Liesl Celliers,
Michael Nesbit,
Somayra Mamsa,
Frank Arfuso,
Sukanya Das,
Frank Köentgen,
Maree Hagan,
Lincoln Codd,
Kirsty Richardson,
Brenton O’Mara,
Rainer K. Scharli,
Laurence Morandeau,
Jonathan C. Gauntlett,
Christopher Leatherday,
J Bouček,
John Mamo
Publication year - 2021
Publication title -
plos biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.127
H-Index - 271
eISSN - 1545-7885
pISSN - 1544-9173
DOI - 10.1371/journal.pbio.3001358
Subject(s) - neurodegeneration , biology , extravasation , alzheimer's disease , inflammation , amyloid (mycology) , apolipoprotein e , amyloid beta , neurovascular bundle , blood–brain barrier , pathology , endocrinology , neuroscience , disease , medicine , immunology , central nervous system , anatomy , botany
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.