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Synthesis of human amyloid restricted to liver results in an Alzheimer disease-like neurodegenerative phenotype
PLoS Biol. 2021 Sep 14;19(9):e3001358. doi: 10.1371/journal.pbio.3001358. eCollection 2021 Sep.
Virginie Lam 1 2, Ryusuke Takechi 1 2, Mark J Hackett 1 3, Roslyn Francis 4 5, Michael Bynevelt 6, Liesl M Celliers 4 7, Michael Nesbit 1 2, Somayra Mamsa 1, Frank Arfuso 1, Sukanya Das 1, Frank Koentgen 8, Maree Hagan 8, Lincoln Codd 9, Kirsty Richardson 10, Brenton O'Mara 4, Rainer K Scharli 11 12, Laurence Morandeau 11 12, Jonathan Gauntlett 8, Christopher Leatherday 13, Jan Boucek 13, John C L Mamo 1 2
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.
