Dataset Information

Identification of neurotoxic cross-linked amyloid-? dimers in the Alzheimer's brain.

ABSTRACT: The primary structure of canonical amyloid-?-protein was elucidated more than 30 years ago, yet the forms of amyloid-? that play a role in Alzheimer's disease pathogenesis remain poorly defined. Studies of Alzheimer's disease brain extracts suggest that amyloid-?, which migrates on sodium dodecyl sulphate polyacrylamide gel electrophoresis with a molecular weight of ?7 kDa (7kDa-A?), is particularly toxic; however, the nature of this species has been controversial. Using sophisticated mass spectrometry and sensitive assays of disease-relevant toxicity we show that brain-derived bioactive 7kDa-A? contains a heterogeneous mixture of covalently cross-linked dimers in the absence of any other detectable proteins. The identification of amyloid-? dimers may open a new phase of Alzheimer's research and allow a better understanding of Alzheimer's disease, and how to monitor and treat this devastating disorder. Future studies investigating the bioactivity of individual dimers cross-linked at known sites will be critical to this effort.

SUBMITTER: Brinkmalm G

PROVIDER: S-EPMC6487330 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Identification of neurotoxic cross-linked amyloid-β dimers in the Alzheimer's brain.

Brinkmalm Gunnar G Hong Wei W Wang Zemin Z Liu Wen W O'Malley Tiernan T TT Sun Xin X Frosch Matthew P MP Selkoe Dennis J DJ Portelius Erik E Zetterberg Henrik H Blennow Kaj K Walsh Dominic M DM

Brain : a journal of neurology 20190501 5

The primary structure of canonical amyloid-β-protein was elucidated more than 30 years ago, yet the forms of amyloid-β that play a role in Alzheimer's disease pathogenesis remain poorly defined. Studies of Alzheimer's disease brain extracts suggest that amyloid-β, which migrates on sodium dodecyl sulphate polyacrylamide gel electrophoresis with a molecular weight of ∼7 kDa (7kDa-Aβ), is particularly toxic; however, the nature of this species has been controversial. Using sophisticated mass spect ...[more]

PMID: 31032851

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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.

Dataset Information

Identification of neurotoxic cross-linked amyloid-? dimers in the Alzheimer's brain.

Publications

Identification of neurotoxic cross-linked amyloid-β dimers in the Alzheimer's brain.

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