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Impaired hepatic amyloid-beta degradation in Alzheimer's disease.

ABSTRACT: Extensive research strongly suggests that amyloid beta (A?) aggregates in the brain have a central role in Alzheimer's disease (AD) pathogenesis. Pathological A? 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? degradation. It is possible alterations of liver function could affect brain A? levels through changes in blood A? concentration. In this study, we hypothesized hepatic A? degradation to be impaired in AD subjects. To test our hypothesis, an A? degradation assay was developed using synthetic fluorescein-labeled A?40 and A?42 spiked into human liver homogenates. A? 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?-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? degradation could be a factor contributing to increased brain A? accumulation and AD.

SUBMITTER: Maarouf CL

PROVIDER: S-EPMC6128628 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Project description:Alzheimer's disease (AD) is the most frequently diagnosed neurodegenerative disorder affecting humans, with advanced age being the most prominent risk factor for developing AD. Despite intense research efforts aimed at elucidating the precise molecular underpinnings of AD, a definitive answer is still lacking. In recent years, consensus has grown that dimerisation of the polypeptide amyloid-beta (Aß), particularly Aß??, plays a crucial role in the neuropathology that characterise AD-affected post-mortem brains, including the large-scale accumulation of fibrils, also referred to as senile plaques. This has led to the realistic hope that targeting Aß?? immunotherapeutically could drastically reduce plaque burden in the ageing brain, thus delaying AD onset or symptom progression. Stochastic modelling is a useful tool for increasing understanding of the processes underlying complex systems-affecting disorders such as AD, providing a rapid and inexpensive strategy for testing putative new therapies. In light of the tool's utility, we developed computer simulation models to examine Aß?? turnover and its aggregation in detail and to test the effect of immunization against Aß dimers.Our model demonstrates for the first time that even a slight decrease in the clearance rate of Aß?? monomers is sufficient to increase the chance of dimers forming, which could act as instigators of protofibril and fibril formation, resulting in increased plaque levels. As the process is slow and levels of A? are normally low, stochastic effects are important. Our model predicts that reducing the rate of dimerisation leads to a significant reduction in plaque levels and delays onset of plaque formation. The model was used to test the effect of an antibody mediated immunological response. Our results showed that plaque levels were reduced compared to conditions where antibodies are not present.Our model supports the current thinking that levels of dimers are important in initiating the aggregation process. Although substantial knowledge exists regarding the process, no therapeutic intervention is on offer that reliably decreases disease burden in AD patients. Computer modelling could serve as one of a number of tools to examine both the validity of reliable biomarkers and aid the discovery of successful intervention strategies.

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Impaired hepatic amyloid-beta degradation in Alzheimer's disease.

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