Several series of studies suggest that the peripheral metabolism of amyloid beta (Aß) is linked to a risk for Alzheimer’s disease (AD). In the blood, more than 90% of Aß is complexed as apolipoprotein, which increases the possibility of a lipoprotein-mediated axis for AD risk.
This study reports that the genetic modification of C57BL / 6J mice engineered to synthesize human Aß only in the liver (hepatocyte-specific human amyloid (HSHA) strain), a pronounced neurodegeneration along with capillary dysfunction, parenchymal Caused extravasation of lipoprotein Aß and neurovascular inflammation. In addition, the HSHA mice showed impaired performance in the passive avoidance test, suggesting impairment of hippocampus-dependent learning. Transmission electron microscopy shows marked neurovascular disorder in HSHA mice. This study provides causal evidence of a lipoprotein Aβ / capillary axis for the onset and progression of a neurodegenerative process.
- The expression of the human APP gene is specifically restricted to the liver of HSHA mice
- Hepatic hAPP induced an age-related increased cerebral uptake of amyloid radiotracers. 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 showed a pronounced neurodegenerative phenotype and brain atrophy
- The restriction of human APP to liver hepatocytes exacerbates cerebral capillary dysfunction and neurovascular inflammation
- The ultrastructural analysis of the brain of HSHA mice showed clear cellular and subcellular degenerative changes
- HSHA mice performed poorly in the passive avoidance test
- HSHA mice exhibited mild transient liver dysfunction
Here we investigated whether an APP-modeled transgenic amyloid strain from mice expressing human APP1 restricted to liver hepatocytes (HSHA) develops a neurodegenerative phenotype that could explain the etiology of AD. Our collective results in HSHA mice on accelerated focal lipocentric CNS aberrations suggest that the peripheral metabolism of TRL-Aβ may be causally associated with a neurodegenerative phenotype. We claim that the interpretation is consistent with findings published decades ago by Alois Alzheimer, which have rarely been taken into account in the context of etiology.
In this study, we expand our understanding of age-associated focal changes in cerebral neutral lipid aggregates through the use of FTIR. In agreement with the Herxheimer staining data showing accelerated LIB formation in HSHA mice, the FTIR analysis showed a significantly greater frequency of triglyceride / cholesteryl esters within the HPF, consistent with the results presented on the association of Lipids with amyloid pathology have been reported during AD in APP / PS1 mice and human clinical tissue
This study provides direct evidence for the first time that the hepatic expression of genes that lead to the synthesis of human Aβ is causally linked to a corruption of the NVU, with cell death and brain atrophy being realized.
This study provides evidence that more subtle chronic interactive effects of the peripheral metabolism of TRL-Aβ with the cerebrovasculature may be sufficient to potentially cause AD.