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Arginine and disordered amyloid-? peptide structures: molecular level insights into the toxicity in Alzheimer's disease.

ABSTRACT: Recent studies present that the single arginine (R) residue in the sequence of A?42 adopts abundant ?-sheet structure and forms stable salt bridges with various residues. Furthermore, experiments proposed that R stimulates the A? assembly and arginine (R) to alanine (A) mutation (R5A) decreases both aggregate formation tendency and the degree of its toxicity. However, the exact roles of R and R5A mutation in the structures of A?42 are poorly understood. Extensive molecular dynamics simulations along with thermodynamic calculations present that R5A mutation impacts the structures and free energy landscapes of the aqueous A?42 peptide. The ?-sheet structure almost disappears in the Ala21-Ala30 region but is more abundant in parts of the central hydrophobic core and C-terminal regions of A?42 upon R5A mutation. More abundant ?-helix is adopted in parts of the N-terminal and mid-domain regions and less prominent ?-helix formation occurs in the central hydrophobic core region of A?42 upon R5A mutation. Interestingly, intramolecular interactions between N- and C-terminal or mid-domain regions disappear upon R5A mutation. The structures of A?42 are thermodynamically less stable and retain reduced compactness upon R5A mutation. R5A mutant-type structure stability increases with more prominent central hydrophobic core and mid-domain or C-terminal region interactions. Based on our results reported in this work, small organic molecules and antibodies that avoid ?-sheet formation in the Ala21-Ala30 region and hinder the intramolecular interactions occurring between the N-terminal and mid-domain or C-terminal regions of A?42 may help to reduce A?42 toxicity in Alzheimer's disease.

SUBMITTER: Coskuner O

PROVIDER: S-EPMC3867960 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Arginine and disordered amyloid-β peptide structures: molecular level insights into the toxicity in Alzheimer's disease.

Coskuner Orkid O Wise-Scira Olivia O

ACS chemical neuroscience 20131008 12

Recent studies present that the single arginine (R) residue in the sequence of Aβ42 adopts abundant β-sheet structure and forms stable salt bridges with various residues. Furthermore, experiments proposed that R stimulates the Aβ assembly and arginine (R) to alanine (A) mutation (R5A) decreases both aggregate formation tendency and the degree of its toxicity. However, the exact roles of R and R5A mutation in the structures of Aβ42 are poorly understood. Extensive molecular dynamics simulations a ...[more]

PMID: 24041422

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Project description:In the more than a century since its identification, Alzheimer's disease has become the archetype of amyloid diseases. The first glimpses of the chemical basis of Alzheimer's disease began with the identification of "amyloid" plaques in the brain in 1892 and extended to the identification of proteinaceous fibrils with "cross-?" structure in 1968. Further efforts led to the discovery of the ?-amyloid peptide, A?, as a 40- or 42-amino acid peptide that is responsible for the plaques and fibrils. At this point, a three-decade-long marathon began to elucidate the structure of the fibrils and identify the molecular basis of Alzheimer's disease. Along the way, an alternative model began to emerge in which small aggregates of A?, called "oligomers", rather than fibrils, are the culprits that lead to neurodegeneration in Alzheimer's disease. This Account describes what is known about the structures of the fibrils and details our research group's efforts to understand the structural, biophysical, and biological properties of the oligomers in amyloid diseases. ?-Sheets are the building blocks of amyloid fibrils and oligomers. Amyloid fibrils generally consist of extended networks of parallel ?-sheets. Amyloid oligomers appear to be more compact enclosed structures, some of which are thought to be composed of antiparallel ?-sheets comprising ?-hairpins. ?-Hairpins are special because their twisted shape, hydrophobic surfaces, and exposed hydrogen-bonding edges impart a unique propensity to form compact assemblies. Our laboratory has developed macrocyclic ?-sheets that are designed to mimic ?-hairpins formed by amyloidogenic peptides and proteins. The ?-hairpin mimics contain two ?-strand peptide fragments linked together at their N- and C-termini by two ?-linked ornithine turn mimics to create a macrocycle. An N-methyl group is installed on one of the ?-strands to prevent uncontrolled aggregation. These design features facilitate crystallization of the ?-hairpin mimics and determination of the X-ray crystallographic structures of the oligomers that they form. During the past few years, our laboratory has elucidated the X-ray crystallographic structures of oligomers formed by ?-hairpin mimics derived from A?, ?-synuclein, and ?2-microglobulin. Out of these three amyloidogenic peptides and proteins, the A? ?-hairpin mimics have provided the most insight into amyloid oligomers. Our studies have revealed a previously undiscovered mode of self-assembly, whereby three A? ?-hairpin mimics assemble to form a triangular trimer. The triangular trimers are remarkable, because they contain two largely hydrophobic surfaces that pack together with other triangular trimers to form higher-order oligomers, such as hexamers and dodecamers. Some of the dodecamers pack in the crystal lattice to form annular porelike assemblies. Some of the ?-hairpin mimics and triangular trimers assemble in solution to form oligomers that recapitulate the crystallographically observed oligomers. These oligomers exhibit toxicity toward neuronally derived cells, recapitulating the toxicity of the oligomers formed by full-length amyloidogenic peptides and proteins. These findings are significant, because they address a gap in understanding the molecular basis of amyloid diseases. We anticipate that these studies will pave the way for developing diagnostics and therapeutics to combat Alzheimer's disease, Parkinson's disease, and other amyloid diseases.

Project description:BACKGROUND: Misfolding and self-assembly of Amyloid-? (A?) peptides into amyloid fibrils is pathologically linked to the development of Alzheimer's disease. Polymorphic A? structures derived from monomers to intermediate oligomers, protofilaments, and mature fibrils have been often observed in solution. Some aggregates are on-pathway species to amyloid fibrils, while the others are off-pathway species that do not evolve into amyloid fibrils. Both on-pathway and off-pathway species could be biologically relevant species. But, the lack of atomic-level structural information for these A? species leads to the difficulty in the understanding of their biological roles in amyloid toxicity and amyloid formation. METHODS AND FINDINGS: Here, we model a series of molecular structures of A? globulomers assembled by monomer and dimer building blocks using our peptide-packing program and explicit-solvent molecular dynamics (MD) simulations. Structural and energetic analysis shows that although A? globulomers could adopt different energetically favorable but structurally heterogeneous conformations in a rugged energy landscape, they are still preferentially organized by dynamic dimeric subunits with a hydrophobic core formed by the C-terminal residues independence of initial peptide packing and organization. Such structural organizations offer high structural stability by maximizing peptide-peptide association and optimizing peptide-water solvation. Moreover, curved surface, compact size, and less populated ?-structure in A? globulomers make them difficult to convert into other high-order A? aggregates and fibrils with dominant ?-structure, suggesting that they are likely to be off-pathway species to amyloid fibrils. These A? globulomers are compatible with experimental data in overall size, subunit organization, and molecular weight from AFM images and H/D amide exchange NMR. CONCLUSIONS: Our computationally modeled A? globulomers provide useful insights into structure, dynamics, and polymorphic nature of A? globulomers which are completely different from A? fibrils, suggesting that these globulomers are likely off-pathway species and explaining the independence of the aggregation kinetics between A? globulomers and fibrils.

Project description:MiRNA molecules are important post-transcriptional regulators of gene expression in the brain function. Altered miRNA profiles could represent a defensive response against the pathogenesis of neurodegenerative disorders, such as Alzheimer's disease (AD). Endogenous miRNAs have lower toxic effects than other gene silencing methods, thus enhancing the expression of defensive miRNA could be an effective therapy. However, little is known about the potential of targeting miRNAs for the treatment of AD. Here, we examined the function of the miR-200 family (miR-200a, -141, -429, -200b, -200c), identified using miRNA microarray analysis of cortical tissue from Tg2576 transgenic mice. In murine primary neurons, we found that upregulation of miR-200b or -200c was induced by the addition of amyloid beta (Aβ). Neurons transfected with miR-200b or -200c reduced secretion of Aβ in conditioned medium. Moreover, mice infused with miR-200b/c into the brain were relieved of memory impairments induced by intracerebroventricular injection of oligomeric Aβ, and demonstrated proper spatial learning in the Barnes maze. To gain further understanding of the relationship between miR-200b/c and Aβ, we identified target mRNAs via an RNA-binding protein immunoprecipitation-microarray assay. Western blot analysis showed that expression of ribosomal protein S6 kinase B1 (S6K1), a candidate target, was inhibited by miR-200c. S6K1, a downstream effector of mammalian target of rapamycin (mTOR), serves as a negative feedback mediator that phosphorylates insulin receptor substrate 1 at serine residues (IRS-1pSer). S6K1-dependent IRS-1pSer suppresses insulin signaling leading to insulin resistance, which is frequently observed in AD brains. Notably, miR-200b/c transfection of SH-SY5Y cells reduced the levels of IRS-1pSer. This finding indicates that miR-200b/c has the potential to alleviate insulin resistance via modulation of S6K1. Taken together, miR-200b/c may contribute to reduce Aβ secretion and Aβ-induced cognitive impairment by promoting insulin signaling.

Dataset Information

Arginine and disordered amyloid-? peptide structures: molecular level insights into the toxicity in Alzheimer's disease.

Publications

Arginine and disordered amyloid-β peptide structures: molecular level insights into the toxicity in Alzheimer's disease.

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