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 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.