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Effect of the English familial disease mutation (H6R) on the monomers and dimers of A?40 and A?42.

ABSTRACT: The self-assembly of the amyloid beta (A?) peptides into senile plaques is the hallmark of Alzheimer's disease. Recent experiments have shown that the English familial disease mutation (H6R) speeds up the fibril formation process of alloforms A?40 and A?42 peptides altering their toxicity to cells. We used all-atom molecular dynamics simulations at microsecond time scales with the OPLS-AA force field and TIP4P explicit water model to study the structural dynamics of the monomer and dimer of H6R sequences of both peptides. The reason behind the self-assembly acceleration is common that upon mutation the net charge is reduced leading to the weaker repulsive interaction between chains that facilitates the peptide association. In addition, our estimation of the solvation free energy shows that the mutation enhances the hydrophobicity of both peptides speeding up their aggregation. However, we can show that the acceleration mechanisms are different for different peptides: the rate of fibril formation of A?42 increases due to increased ?-structure at the C-terminal in both monomer and dimer and enhanced stability of salt bridge Asp23-Lys28 in monomer, while the enhancement of turn at residues 25-29 and reduction of coil in regions 10-13, 26-19, and 30-34 would play the key role for A?40. Overall, our study provides a detailed atomistic picture of the H6R-mediated conformational changes that are consistent with the experimental findings and highlights the important role of the N-terminal in A? peptide aggregation.

SUBMITTER: Viet MH

PROVIDER: S-EPMC4140585 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Effect of the English familial disease mutation (H6R) on the monomers and dimers of Aβ40 and Aβ42.

Viet Man Hoang MH Nguyen Phuong H PH Derreumaux Philippe P Li Mai Suan MS

ACS chemical neuroscience 20140630 8

The self-assembly of the amyloid beta (Aβ) peptides into senile plaques is the hallmark of Alzheimer's disease. Recent experiments have shown that the English familial disease mutation (H6R) speeds up the fibril formation process of alloforms Aβ40 and Aβ42 peptides altering their toxicity to cells. We used all-atom molecular dynamics simulations at microsecond time scales with the OPLS-AA force field and TIP4P explicit water model to study the structural dynamics of the monomer and dimer of H6R ...[more]

PMID: 24949887

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Project description:ObjectiveThe diagnostic accuracy of cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD) must be improved before widespread clinical use. This study aimed to determine whether CSF A?42/A?40 and A?42/A?38 ratios are better diagnostic biomarkers of AD during both predementia and dementia stages in comparison to CSF A?42 alone.MethodsThe study comprised three different cohorts (n = 1182) in whom CSF levels of A?42, A?40, and A?38 were assessed. CSF A?s were quantified using three different immunoassays (Euroimmun, Meso Scale Discovery, Quanterix). As reference standard, we used either amyloid ((18)F-flutemetamol) positron emission tomography (PET) imaging (n = 215) or clinical diagnosis (n = 967) of well-characterized patients.ResultsWhen using three different immunoassays in cases with subjective cognitive decline and mild cognitive impairment, the CSF A?42/A?40 and A?42/A?38 ratios were significantly better predictors of abnormal amyloid PET than CSF A?42. Lower A?42, A?42/A?40, and A?42/A?38 ratios, but not A?40 and A?38, correlated with smaller hippocampal volumes measured by magnetic resonance imaging. However, lower A?38, A?40, and A?42, but not the ratios, correlated with non-AD-specific subcortical changes, that is, larger lateral ventricles and white matter lesions. Further, the A?42/A?40 and A?42/A?38 ratios showed increased accuracy compared to A?42 when distinguishing AD from dementia with Lewy bodies or Parkinson's disease dementia and subcortical vascular dementia, where all A?s (including A?42) were decreased.InterpretationThe CSF A?42/A?40 and A?42/A?38 ratios are significantly better than CSF A?42 to detect brain amyloid deposition in prodromal AD and to differentiate AD dementia from non-AD dementias. The ratios reflect AD-type pathology better, whereas decline in CSF A?42 is also associated with non-AD subcortical pathologies. These findings strongly suggest that the ratios rather than CSF A?42 should be used in the clinical work-up of AD.

Dataset Information

Effect of the English familial disease mutation (H6R) on the monomers and dimers of A?40 and A?42.

Publications

Effect of the English familial disease mutation (H6R) on the monomers and dimers of Aβ40 and Aβ42.

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