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Induced beta-barrel formation of the Alzheimer's Abeta25-35 oligomers on carbon nanotube surfaces: implication for amyloid fibril inhibition.

ABSTRACT: Recent experimental studies show that carbon nanotubes impact the aggregation process of proteins associated with neurodegenerative diseases. However, the details of molecular interactions between proteins and carbon nanotubes are still not well understood. In this study, we investigate the initial adsorption features and dynamics of the Alzheimer's amyloid-beta peptide spanning residues 25-35 (Abeta25-35) on a single-walled carbon nanotube (SWNT) surface using fully atomic molecular dynamics simulations (MD) in explicit solvent. The initial configurations of the Abeta25-35 peptides consist of two preformed bilayer beta-sheets, each with four or five beta-strands in parallel or mixed antiparallel-parallel orientations. Our simulations show, for what we believe is the first time, that two disjointed Abeta25-35 beta-sheets with mixed antiparallel-parallel strands can assemble into beta-barrels wrapping the SWNT. In contrast, both simulations of Abeta25-35 without SWNT, and simulations of SWNT-Abeta25-35 with purely parallel beta-strands, lead to disordered aggregates. We find that Abeta25-35 beta-barrel formation involves at least two steps: i), curving of the Abeta25-35 beta-sheets as a result of strong hydrophobic interactions with carbon nanotube concomitantly with dehydration of the SWNT-peptide interface; and ii), intersheet backbone hydrogen bond formation with fluctuating intrasheet hydrogen bonds. Detailed analysis of the conversion shows that beta-barrel formation on SWNT surface results from the interplay of dehydration and peptide-SWNT/peptide-peptide interactions. Implications of our results on amyloid fibril inhibition are discussed.

SUBMITTER: Fu Z

PROVIDER: S-EPMC2749794 | biostudies-literature | 2009 Sep

REPOSITORIES: biostudies-literature

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Induced beta-barrel formation of the Alzheimer's Abeta25-35 oligomers on carbon nanotube surfaces: implication for amyloid fibril inhibition.

Fu Zhaoming Z Luo Yin Y Derreumaux Philippe P Wei Guanghong G

Biophysical journal 20090901 6

Recent experimental studies show that carbon nanotubes impact the aggregation process of proteins associated with neurodegenerative diseases. However, the details of molecular interactions between proteins and carbon nanotubes are still not well understood. In this study, we investigate the initial adsorption features and dynamics of the Alzheimer's amyloid-beta peptide spanning residues 25-35 (Abeta25-35) on a single-walled carbon nanotube (SWNT) surface using fully atomic molecular dynamics si ...[more]

PMID: 19751686

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Project description:Alzheimer's disease begins about two decades before the onset of symptoms or neuron death, and is believed to be caused by pathogenic amyloid-? aggregates that initiate a cascade of molecular events culminating in widespread neurodegeneration. The microtubule binding protein tau may mediate the effects of amyloid-? in this cascade. Amyloid plaques comprised of insoluble, fibrillar amyloid-? aggregates are the most characteristic feature of Alzheimer's disease. However, the correspondence between the distribution of plaques and the pattern of neurodegeneration is tenuous. This discrepancy has stimulated the investigation of other amyloid-? aggregates, including soluble amyloid-? oligomers. Different soluble amyloid-? oligomers have been studied in several mouse models, but not systematically in humans. Here, we measured three amyloid-? oligomers previously described in mouse models-amyloid-? trimers, A?*56 and amyloid-? dimers-in brain tissue from 75 cognitively intact individuals, ranging from young children to the elderly, and 58 impaired subjects with mild cognitive impairment or probable Alzheimer's disease. As in mouse models, where amyloid-? trimers appear to be the fundamental amyloid-? assembly unit of A?*56 and are present in young mice prior to memory decline, amyloid-? trimers in humans were present in children and adolescents; their levels rose gradually with age and were significantly above baseline in subjects in their 70s. A?*56 levels were negligible in children and young adults, rose significantly above baseline in subjects in their 40s and increased steadily thereafter. Amyloid-? dimers were undetectable until subjects were in their 60s; their levels then increased sharply and correlated with plaque load. Remarkably, in cognitively intact individuals we found strong positive correlations between A?*56 and two pathological forms of soluble tau (tau-CP13 and tau-Alz50), and negative correlations between A?*56 and two postsynaptic proteins (drebrin and fyn kinase), but none between amyloid-? dimers or amyloid-? trimers and tau or synaptic proteins. Comparing impaired with age-matched unimpaired subjects, we found the highest levels of amyloid-? dimers, but the lowest levels of A?*56 and amyloid-? trimers, in subjects with probable Alzheimer's disease. In conclusion, in cognitively normal adults A?*56 increased ahead of amyloid-? dimers or amyloid-? trimers, and pathological tau proteins and postsynaptic proteins correlated with A?*56, but not amyloid-? dimers or amyloid-? trimers. We propose that A?*56 may play a pathogenic role very early in the pathogenesis of Alzheimer's disease.

Dataset Information

Induced beta-barrel formation of the Alzheimer's Abeta25-35 oligomers on carbon nanotube surfaces: implication for amyloid fibril inhibition.

Publications

Induced beta-barrel formation of the Alzheimer's Abeta25-35 oligomers on carbon nanotube surfaces: implication for amyloid fibril inhibition.

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