Dataset Information

Differences in ?-strand populations of monomeric A?40 and A?42.

ABSTRACT: Using homonuclear (1)H NOESY spectra, with chemical shifts, (3)JH(N)H(?) scalar couplings, residual dipolar couplings, and (1)H-(15)N NOEs, we have optimized and validated the conformational ensembles of the amyloid-? 1-40 (A?40) and amyloid-? 1-42 (A?42) peptides generated by molecular dynamics simulations. We find that both peptides have a diverse set of secondary structure elements including turns, helices, and antiparallel and parallel ?-strands. The most significant difference in the structural ensembles of the two peptides is the type of ?-hairpins and ?-strands they populate. We find that A?42 forms a major antiparallel ?-hairpin involving the central hydrophobic cluster residues (16-21) with residues 29-36, compatible with known amyloid fibril forming regions, whereas A?40 forms an alternative but less populated antiparallel ?-hairpin between the central hydrophobic cluster and residues 9-13, that sometimes forms a ?-sheet by association with residues 35-37. Furthermore, we show that the two additional C-terminal residues of A?42, in particular Ile-41, directly control the differences in the ?-strand content found between the A?40 and A?42 structural ensembles. Integrating the experimental and theoretical evidence accumulated over the last decade, it is now possible to present monomeric structural ensembles of A?40 and A?42 consistent with available information that produce a plausible molecular basis for why A?42 exhibits greater fibrillization rates than A?40.

SUBMITTER: Ball KA

PROVIDER: S-EPMC3686344 | biostudies-other | 2013 Jun

REPOSITORIES: biostudies-other

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Publications

Differences in β-strand populations of monomeric Aβ40 and Aβ42.

Ball K Aurelia KA Phillips Aaron H AH Wemmer David E DE Head-Gordon Teresa T

Biophysical journal 20130601 12

Using homonuclear (1)H NOESY spectra, with chemical shifts, (3)JH(N)H(α) scalar couplings, residual dipolar couplings, and (1)H-(15)N NOEs, we have optimized and validated the conformational ensembles of the amyloid-β 1-40 (Aβ40) and amyloid-β 1-42 (Aβ42) peptides generated by molecular dynamics simulations. We find that both peptides have a diverse set of secondary structure elements including turns, helices, and antiparallel and parallel β-strands. The most significant difference in the struct ...[more]

PMID: 23790380

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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

Differences in ?-strand populations of monomeric A?40 and A?42.

Publications

Differences in β-strand populations of monomeric Aβ40 and Aβ42.

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