Dataset Information

Conformational Change of Amyloid-? 40 in Association with Binding to GM1-Glycan Cluster.

ABSTRACT: Aggregates of amyloid-? (A?) peptide are well known to be the causative substance of Alzheimer's disease (AD). Recent studies showed that monosialotetrahexosylganglioside (GM1) clusters induce the pathological aggregation of A? peptide responsible for the onset and development of AD. However, the effect of GM1-glycan cluster on A? conformations has yet to be clarified. Interactions between A? peptide and GM1-glycan cluster is important for the earliest stage of the toxic aggregation on GM1 cluster. Here, we performed all-atom molecular dynamics (MD) simulations of A?40 on a recently developed artificial GM1-glycan cluster. The artificial GM1-glycan cluster facilitates the characterization of interactions between A?40 and multiple GM1-glycans. We succeeded in observing the binding of A?40 to the GM1-glycan cluster in all of our MD simulations. Results obtained from these MD simulations indicate the importance of HHQ (13-15) segment of A?40 for the GM1-glycan cluster recognition. This result is consistent with previous experimental studies regarding the glycan recognition of A? peptide. The recognition mechanism of HHQ (13-15) segment is mainly explained by non-specific stacking interactions between side-chains of histidine and rings of sugar residues, in which the HHQ regime forms coil and bend structures. Moreover, we found that A?40 exhibits helix structures at C-terminal side on the GM1-glycan cluster. The helix formation is the initial stage of the pathological aggregation at ceramide moieties of GM1 cluster. The binding of Lys28 to Neu triggers the helix formation at C-terminus side because the formation of a salt bridge between Lys28 and Neu leads to change of intrachain interactions of A?40. Our findings suggest that the pathological helix formation of A?40 is initiated at GM1-glycan moieties rather than lipid ceramide moieties.

SUBMITTER: Tachi Y

PROVIDER: S-EPMC6497634 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Conformational Change of Amyloid-β 40 in Association with Binding to GM1-Glycan Cluster.

Tachi Yuhei Y Okamoto Yuko Y Okumura Hisashi H

Scientific reports 20190502 1

Aggregates of amyloid-β (Aβ) peptide are well known to be the causative substance of Alzheimer's disease (AD). Recent studies showed that monosialotetrahexosylganglioside (GM1) clusters induce the pathological aggregation of Aβ peptide responsible for the onset and development of AD. However, the effect of GM1-glycan cluster on Aβ conformations has yet to be clarified. Interactions between Aβ peptide and GM1-glycan cluster is important for the earliest stage of the toxic aggregation on GM1 clust ...[more]

PMID: 31048748

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Project description:IntroductionThe identification of early, preferably presymptomatic, biomarkers and true etiologic factors for Alzheimer's disease (AD) is the first step toward establishing effective primary and secondary prevention programs. Consequently, the search for a relatively inexpensive and harmless biomarker for AD continues. Despite intensive research worldwide, to date there is no definitive plasma or blood biomarker indicating high or low risk of conversion to AD.MethodsMagnetic resonance imaging and β-amyloid (Aβ) levels in three blood compartments (diluted in plasma, undiluted in plasma and cell-bound) were measured in 96 subjects (33 with mild cognitive impairment, 14 with AD and 49 healthy controls). Pearson correlations were completed between 113 regions of interest (ROIs) (45 subcortical and 68 cortical) and Aβ levels. Pearson correlation analyses adjusted for the covariates age, sex, apolipoprotein E (ApoE), education and creatinine levels showed neuroimaging ROIs were associated with Aβ levels. Two statistical methods were applied to study the major relationships identified: (1) Pearson correlation with phenotype added as a covariate and (2) a meta-analysis stratified by phenotype. Neuroimaging data and plasma Aβ measurements were taken from 630 Alzheimer's Disease Neuroimaging Initiative (ADNI) subjects to be compared with our results.ResultsThe left hippocampus was the brain region most correlated with Aβ(1-40) bound to blood cell pellets (partial correlation (pcor) = -0.37, P = 0.0007) after adjustment for the covariates age, gender and education, ApoE and creatinine levels. The correlation remained almost the same (pcor = -0.35, P = 0.002) if phenotype is also added as a covariate. The association between both measurements was independent of cognitive status. The left hemisphere entorhinal cortex also correlated with Aβ(1-40) cell-bound fraction. AB128 and ADNI plasma Aβ measurements were not related to any brain morphometric measurement.ConclusionsAssociation of cell-bound Aβ(1-40) in blood with left hippocampal volume was much stronger than previously observed in Aβ plasma fractions. If confirmed, this observation will require careful interpretation and must be taken into account for blood amyloid-based biomarker development.

Dataset Information

Conformational Change of Amyloid-? 40 in Association with Binding to GM1-Glycan Cluster.

Publications

Conformational Change of Amyloid-β 40 in Association with Binding to GM1-Glycan Cluster.

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