Impaired Hepatic Amyloid-Beta Degradation In Alzheimer'S Disease

Extensive research strongly suggests that amyloid beta (A beta) aggregates in the brain have a central role in Alzheimer's disease (AD) pathogenesis. Pathological A beta deposition is likely due to an altered balance between overproduction and elimination. Rodent studies have suggested that the liver has a major role in A beta degradation. It is possible alterations of liver function could affect brain A beta levels through changes in blood A beta concentration. In this study, we hypothesized hepatic A beta degradation to be impaired in AD subjects. To test our hypothesis, an A beta degradation assay was developed using synthetic fluorescein-labeled A beta 40 and A beta 42 spiked into human liver homogenates. A beta degradation rates were lower in AD-derived homogenates as compared with those from non-demented (ND) control subjects, even after accounting for such covariates as age, sex, and APOE genotype. The protein expression of potential A beta-degrading enzymes were also examined. Neprilysin levels were not different in AD liver samples, while cathepsin D and insulin-degrading enzyme were significantly altered in AD subjects. The results support the possibility that impaired hepatic A beta degradation could be a factor contributing to increased brain A beta accumulation and AD.