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.

This study reports 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.

 

Results

  • Human APP gene expression is restricted specifically to the liver of HSHA mice
  • Hepatic-hAPP induced an age-associated increased cerebral uptake of amyloid radiotracer Liver-specific hAPP increased plasma and brain TRL-hAβ
  • Hepatic APP expression in HSHA mice causes aberrant AD-like accumulation of neutral lipids in the brain 
  • HSHA mice exhibited a marked neurodegenerative phenotype and brain atrophy 
  • Restriction of human APP to liver hepatocytes exacerbates cerebral capillary dysfunction and neurovascular inflammation
  • Ultrastructure analysis of the brains of HSHA mice revealed marked cellular and subcellular degenerative changes
  •  HSHA mice showed poorer performance in passive avoidance test
  •  HSHA mice indicated transient modest liver dysfunction
 

Discussion

 
Here, we assessed whether an APP-modelled transgenic amyloid strain of mice with expression of human APP1 restricted to liver hepatocytes (HSHA) develops a neurodegenerative phenotype that could explain aetiology of AD. Our collective findings in HSHA mice of accelerated focal lipocentric CNS aberrations suggest that the peripheral metabolism of TRL-Aβ may be causally associated with a neurodegenerative phenotype. We contend the interpretation is consistent with findings published by Alois Alzheimer decades ago that have been rarely considered in the context of aetiology. 
 
In this study, we extend our understanding of age-associated focal changes in cerebral neutral lipid aggregates by utilising FTIR. Consistent with the Herxheimer staining data showing accelerated LIB formation in HSHA mice, FTIR analysis showed a significantly greater abundance of triglyceride/cholesteryl-esters within the HPF, consistent with findings reported for the association of lipids with amyloid pathology during AD in APP/PS1 mice and clinical human tissue
 
This study provides, for the first time, direct evidence that hepatic expression of genes leading to the synthesis of human-Aβ is causally associated with corruption of the NVU, with cell death and brain atrophy realised. 
 

This study provides evidence that more subtle chronic interactive effects of peripheral metabolism of TRL-Aβ with the cerebrovasculature may be sufficient to potentially cause AD.


 

 

View Open Access Research Article in PLOS Biology