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Quantitative analysis of intrinsic and extrinsic factors in the aggregation mechanism of Alzheimer-associated Aβ-peptide.

ABSTRACT: Disease related mutations and environmental factors are key determinants of the aggregation mechanism of the amyloid-β peptide implicated in Alzheimer's disease. Here we present an approach to investigate these factors through acquisition of highly reproducible data and global kinetic analysis to determine the mechanistic influence of intrinsic and extrinsic factors on the Aβ aggregation network. This allows us to translate the shift in macroscopic aggregation behaviour into effects on the individual underlying microscopic steps. We apply this work-flow to the disease-associated Aβ42-A2V variant, and to a variation in pH as examples of an intrinsic and an extrinsic perturbation. In both cases, our data reveal a shift towards a mechanism in which a larger fraction of the reactive flux goes via a pathway that generates potentially toxic oligomeric species in a fibril-catalyzed reaction. This is in agreement with the finding that Aβ42-A2V leads to early-onset Alzheimer's disease and enhances neurotoxicity.

SUBMITTER: Meisl G

PROVIDER: S-EPMC4725935 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Quantitative analysis of intrinsic and extrinsic factors in the aggregation mechanism of Alzheimer-associated Aβ-peptide.

Meisl Georg G Yang Xiaoting X Frohm Birgitta B Knowles Tuomas P J TP Linse Sara S

Scientific reports 20160113

Disease related mutations and environmental factors are key determinants of the aggregation mechanism of the amyloid-β peptide implicated in Alzheimer's disease. Here we present an approach to investigate these factors through acquisition of highly reproducible data and global kinetic analysis to determine the mechanistic influence of intrinsic and extrinsic factors on the Aβ aggregation network. This allows us to translate the shift in macroscopic aggregation behaviour into effects on the indiv ...[more]

PMID: 26758487

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Project description:BACKGROUND:Sputum remains the most preferred specimen for detection of Mycobacterium tuberculosis due to its non-invasive method of production. Good quality sputum specimen is essential for accurate diagnosis of pulmonary tuberculosis (PTB). It is therefore imperative to assess factors that are related to the production of sputum that is of the best quality. OBJECTIVE:We assessed the intrinsic and extrinsic characteristics of presumed tuberculosis patients and the quality of sputum they produced. METHODS:This was a cross-sectional study in which consenting enrolled presumed tuberculosis patients were subjected to medical examination and a structured questionnaire administered to collect clinical history, demographic information, environmental and behavioral characteristics. The enrolled participants were instructed on how to collect spot and morning sputum specimens for macroscopic and microscopic assessment to determine any association. RESULTS:A total of 309 patients were enrolled into the study with an even distribution on gender (50.5% males). Of these, 202 (65.3%) submitted both a spot and a morning specimen for analysis. On macroscopic examination, 70% spot and 68% morning sputum were characterized as good quality (Purulent/mucoid). The factors associated (p<0.05) with quality specimen included both intrinsic and extrinsic factors. The intrinsic factors included: difficulty in breathing, presence of conjunctivitis and knowledge of the disease whereas the only extrinsic factor associated with production of good quality sputum for tuberculosis diagnosis was time taken by patient to seek tuberculosis treatment after occurrence of any of the TB symptoms. CONCLUSION:Both intrinsic and extrinsic factors affected the quality of sputum produced by presumed tuberculosis patients. Clinical and behavioral characteristics including conjunctivitis, difficulty in breathing and delay in seeking treatment were important factors that determined the production of good quality sputum specimens, while knowledge of tuberculosis disease did not compel presumed tuberculosis patients to produce good quality sputum for diagnosis of the disease.

Project description:The growth mechanism of β-amyloid (Aβ) peptide fibrils was studied by a physics-based coarse-grained united-residue model and molecular dynamics (MD) simulations. To identify the mechanism of monomer addition to an Aβ(1-40) fibril, we placed an unstructured monomer at a distance of 20 Å from a fibril template and allowed it to interact freely with the latter. The monomer was not biased towards fibril conformation by either the force field or the MD algorithm. With the use of a coarse-grained model with replica-exchange molecular dynamics, a longer timescale was accessible, making it possible to observe how the monomers probe different binding modes during their search for the fibril conformation. Although different assembly pathways were seen, they all follow a dock-lock mechanism with two distinct locking stages, consistent with experimental data on fibril elongation. Whereas these experiments have not been able to characterize the conformations populating the different stages, we have been able to describe these different stages explicitly by following free monomers as they dock onto a fibril template and to adopt the fibril conformation (i.e., we describe fibril elongation step by step at the molecular level). During the first stage of the assembly ("docking"), the monomer tries different conformations. After docking, the monomer is locked into the fibril through two different locking stages. In the first stage, the monomer forms hydrogen bonds with the fibril template along one of the strands in a two-stranded β-hairpin; in the second stage, hydrogen bonds are formed along the second strand, locking the monomer into the fibril structure. The data reveal a free-energy barrier separating the two locking stages. The importance of hydrophobic interactions and hydrogen bonds in the stability of the Aβ fibril structure was examined by carrying out additional canonical MD simulations of oligomers with different numbers of chains (4-16 chains), with the fibril structure as the initial conformation. The data confirm that the structures are stabilized largely by hydrophobic interactions and show that intermolecular hydrogen bonds are highly stable and contribute to the stability of the oligomers as well.

Dataset Information

Quantitative analysis of intrinsic and extrinsic factors in the aggregation mechanism of Alzheimer-associated Aβ-peptide.

Publications

Quantitative analysis of intrinsic and extrinsic factors in the aggregation mechanism of Alzheimer-associated Aβ-peptide.

Similar Datasets

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