Association of Highly Compact Type II Diabetes Related Islet Amyloid Polypeptide Intermediate Species at Physiological Temperature Revealed by Diffusion NMR Spectroscopy

Soong, Ronald; Brender, Jeffrey R.; Macdonald, Peter M.; Ramamoorthy, Ayyalusamy

doi:10.1021/ja900285z

Cited by 144 publications

(193 citation statements)

References 80 publications

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“…This suggests that the energy of nucleation is high, and the free energy is a relatively steep function of the aggregate size for subnuclear particles (28,40). We note that a similar absence of small oligomers, despite the presence of monomers and large aggregates (ϳ100 nm), has also been observed for another amyloidogenic protein, IAPP (41).…”

Section: Discussionsupporting

confidence: 79%

Nature of the Amyloid-β Monomer and the Monomer-Oligomer Equilibrium

Nag

Sarkar

Banerjee

et al. 2011

Journal of Biological Chemistry

167

166

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The monomer to oligomer transition initiates the aggregation and pathogenic transformation of Alzheimer amyloid-␤ (A␤) peptide. However, the monomeric state of this aggregationprone peptide has remained beyond the reach of most experimental techniques, and a quantitative understanding of this transition is yet to emerge. Here, we employ single-molecule level fluorescence tools to characterize the monomeric state and the monomer-oligomer transition at physiological concentrations in buffers mimicking the cerebrospinal fluid (CSF). Our measurements show that the monomer has a hydrodynamic radius of 0.9 ؎ 0.1 nm, which confirms the prediction made by some of the in silico studies. Surprisingly, at equilibrium, both A␤ 40 and A␤ 42 remain predominantly monomeric up to 3 M, above which it forms large aggregates. This concentration is much higher than the estimated concentrations in the CSF of either normal or diseased brains. If A␤ oligomers are present in the CSF and are the key agents in Alzheimer pathology, as is generally believed, then these must be released in the CSF as preformed entities. Although the oligomers are thermodynamically unstable, we find that a large kinetic barrier, which is mostly entropic in origin, strongly impedes their dissociation. Thermodynamic principles therefore allow the development of a pharmacological agent that can catalytically convert metastable oligomers into nontoxic monomers.Alzheimer disease (AD) 2 is a degenerative brain disorder that is associated with the presence of extracellular aggregates of amyloid-␤ (A␤) (1), which is an ϳ4.5-kDa peptide containing 39 -42 residues. Recent studies indicate that small soluble oligomers are key to A␤ toxicity (2-4). In the AD brain, both A␤ monomers and dimers have been isolated, and the dimers have been shown to impair synaptic plasticity in mouse hippocampal slices (5). In contrast, A␤ monomers have been shown to be devoid of neurotoxicity (5) and have in fact been suggested to be neuroprotective (6, 7). The monomer to oligomer transition is therefore not only the obligatory first event of aggregation, it is also the key event determining the transformation of a benign protein to a neurotoxic one.We address this transition from a thermodynamic viewpoint: an aggregation-capable molecule should have a defined equilibrium between monomers and dimers (or oligomers), such that it is primarily monomeric below a certain concentration. Any oligomer-enriched solution prepared below such a concentration must be thermodynamically unstable and must dissociate to monomers at a given rate. To understand AD in terms of A␤ aggregation, we need to understand how this concentration compares with the in vivo concentrations of A␤ (which is estimated to be Ͻ Ͻ1 M) (8 -11) and what the kinetics of A␤ oligomer dissociation is.However, experiments probing the monomer to oligomer transition have been difficult to perform due to the low concentration at which this transition most likely occurs, and they have yielded rather confusing results. Some studies have ...

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Section: Discussionsupporting

confidence: 79%

Nature of the Amyloid-β Monomer and the Monomer-Oligomer Equilibrium

Nag

Sarkar

Banerjee

et al. 2011

Journal of Biological Chemistry

167

166

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“…29,70,71,[81][82][83][84] The Aβ barrel is similar to the cytotoxic channel formed by the β-cytolytic antimicrobial PG-1 peptides. Recent studies showed that octameric and decameric β-sheet channels of PG-1 divided into four to five Fig.…”

Section: Discussionmentioning

confidence: 99%

“…However, this does not apply to all amyloid channels. Islet amyloid polypeptide (also known as amylin) can induce other membrane pore types, such as toroidal membrane pores, 82 depending on the outward-facing amino acid sequence interacting with the bilayer. Amylin also forms ion channels, as demonstrated in earlier work.…”

Section: Discussionmentioning

confidence: 99%

β-Barrel Topology of Alzheimer's β-Amyloid Ion Channels

Jang

Arce

Ramachandran

et al. 2010

Journal of Molecular Biology

123

180

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Emerging evidence supports the ion channel mechanism for Alzheimer's disease pathophysiology wherein small β-amyloid (Aβ) oligomers insert into the cell membrane, forming toxic ion channels and destabilizing the cellular ionic homeostasis. Solid-state NMR-based data of amyloid oligomers in solution indicate that they consist of a double-layered β-sheets where each monomer folds into β-strand-turn-β-strand and the monomers are stacked atop each other. In the membrane, Aβ peptides are proposed to be β-type structures. Experimental structural data available from atomic force microscopy (AFM) imaging of Aβ oligomers in membranes reveal heterogeneous channel morphologies. Previously, we modeled the channels in a non-tilted organization, parallel with the cross-membrane normal. Here, we modeled a β-barrel-like organization. β-Barrels are common in transmembrane toxin pores, typically consisting of a monomeric chain forming a pore, organized in a single-layered β-sheet with antiparallel β-strands and a right-handed twist. Our explicit solvent molecular dynamics simulations of a range of channel sizes and polymorphic turns and comparisons of these with AFM image dimensions support a β-barrel channel organization. Different from the transmembrane β-barrels where the monomers are folded into a circular β-sheet with antiparallel β-strands stabilized by the connecting loops, these Aβ barrels consist of multimeric chains forming double β-sheets with parallel β-strands, where the strands of each monomer are connected by a turn. Although the Aβ barrels adopt the right-handed β-sheet twist, the barrels still break into heterogeneous, loosely attached subunits, in good agreement with AFM images and previous modeling. The subunits appear mobile, allowing unregulated, hence toxic, ion flux.

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“…[16] Finally, after 30 h of incubation, the morphology of hIAPPmembrane systems, which consist of rows of cylinders with long-range order in the XY plain, appears to be very similar to the one observed for Ab 1-40 fibrils. [22] A possible mechanism for membrane damage and fibril growth by hIAPP based on our AFM, QCM-D and fluorescence results combined with NMR spectroscopy [23] is shown in Figure 4. From this model emerges a scenario in which the formation of mature fibrils does not appear to be the cause of membrane damage.…”

mentioning

confidence: 92%

Self‐Assembling Pathway of HiApp Fibrils within Lipid Bilayers

et al. 2010

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The performance of bottom‐contact thin‐film transistor (TFT) structures lags behind that of top‐contact structures owing to the far greater contact resistance. The major sources of the contact resistance in bottom‐contact TFTs are believed to reflect a combination of non‐optimal semiconductor growth morphology on the metallic contact surface and the limited available charge injection area versus top‐contact geometries. As a part of an effort to understand the sources of high charge injection barriers in n‐channel TFTs, the influence of thiol metal contact treatment on the molecular‐level structures of such interfaces is investigated using hexamethyldisilazane (HMDS)‐treated SiO2 gate dielectrics. The focus is on the self‐assembled monolayer (SAM) contact surface treatment methods for bottom‐contact TFTs based on two archetypical n‐type semiconductors, α,ω‐diperfluorohexylquarterthiophene (DFH‐4T) and N,N′bis(n‐octyl)‐dicyanoperylene‐3,4:9,10‐bis(dicarboximide) (PDI‐8CN2). TFT performance can be greatly enhanced, to the level of the top contact device performance in terms of mobility, on/off ratio, and contact resistance. To analyze the molecular‐level film structural changes arising from the contact surface treatment, surface morphologies are characterized by atomic force microscopy (AFM) and scanning tunneling microscopy (STM). The high‐resolution STM images show that the growth orientation of the semiconductor molecules at the gold/SAM/semiconductor interface preserves the molecular long axis orientation along the substrate normal. As a result, the film microstructure is well‐organized for charge transport in the interfacial region.

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Association of Highly Compact Type II Diabetes Related Islet Amyloid Polypeptide Intermediate Species at Physiological Temperature Revealed by Diffusion NMR Spectroscopy

Cited by 144 publications

References 80 publications

Nature of the Amyloid-β Monomer and the Monomer-Oligomer Equilibrium

Nature of the Amyloid-β Monomer and the Monomer-Oligomer Equilibrium

β-Barrel Topology of Alzheimer's β-Amyloid Ion Channels

Self‐Assembling Pathway of HiApp Fibrils within Lipid Bilayers

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