Alzheimer?s Disease: Soluble Oligomeric A?(1?40) Peptide in Membrane Mimic Environment from Solution NMR and Circular Dichroism Studies

Mandal, Pravat K.; Pettegrew, Jay W.

doi:10.1007/s11064-004-7035-1

Cited by 60 publications

(69 citation statements)

References 33 publications

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“…In the case of the native peptide Ab (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28) in the SDS micelles 33 or in 60% TFE, 47 only one set of NMR crosspeaks was observed, and the peptide was found to form stable a-helical structure. NMR investigations of longer Ab peptides 25,32,34,35,40,[54][55][56][57][58][59] also did not reveal the existence of minor conformations. The minor crosspeaks for some residues at the N-terminus were observed only on the 2D NMR spectra of the Ab(1-42) peptide.…”

Section: Discussionmentioning

confidence: 99%

“…To form regular micelles and ensure that the investigated peptides were indeed micelle-bound, we used a high concentration of SDS-D 25 , which is high above the critical micelle concentrations of SDS (8.3 mM). The final pH of the sample was adjusted to 6 using 1M NaOH and 1M HCl.…”

Section: Nmr Studiesmentioning

confidence: 99%

“…Moreover, there is some evidence that changes in membrane structure can trigger a cascade of events leading to the formation of toxic, soluble b-sheet oligomers of Ab. 25 We describe here the conformational analysis of Ab fragments in a membrane-mimicking (sodium dodecylsulfate, SDS) environment using circular dichroism (CD) spectropolarimetry and NMR spectroscopy. CD studies were carried out in nonmicellar SDS concentration and in the presence of SDS micelles, whereas the NMR experiments were performed only in micellar concentration.…”

Section: Introductionmentioning

confidence: 99%

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Conformational solution studies of the SDS micelle‐bound 11‐28 fragment of two Alzheimer's β‐amyloid variants (E22K and A21G) using CD, NMR, and MD techniques

et al. 2007

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The beta-amyloid (Abeta) is the major peptide constituent of neuritic plaques in Alzheimer's disease (AD) and its aggregation is believed to play a central role in the pathogenesis of the disease. Naturally occurring mutations resulting in changes in the Abeta sequence (pos. 21-23) are associated with familial AD-like diseases with extensive cerebrovascular pathology. It was proved that the mutations alter the aggregation ability of Abeta and its neurotoxicity. Among five mutations at positions 21-23 there are two mutations with distinct clinical characteristics and potentially distinct pathogenic mechanism-the Italian (E22K) and the Flemish (A21G) mutations. In our studies we have examined the structures of the 11-28 fragment of the Italian and Flemish Abeta variants. The fragment was chosen because it has been shown to be the most important for amyloid fibril formation. The detailed structure of both variants Abeta(11-28) was determined using CD, 2D NMR, and molecular dynamics techniques under water-SDS micelle conditions. The NMR analysis revealed two distinct sets of proton resonances for the peptides. The studies of both peptides pointed out the existence of well-defined alpha-helical conformation in the Italian mutant, whereas the Flemish was found to be unstructured with the possibility of a bent structure in the central part of the peptide.

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Section: Discussionmentioning

confidence: 99%

Section: Nmr Studiesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Conformational solution studies of the SDS micelle‐bound 11‐28 fragment of two Alzheimer's β‐amyloid variants (E22K and A21G) using CD, NMR, and MD techniques

et al. 2007

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“…In this context, previous studies devoted to Aβ in a membrane environment have used either liposomes (8)(9)(10)(11)(12) or detergent micelles (13)(14)(15). The study of Aβ reconstituted in liposomes has been mainly through electrical recording using planar lipid bilayers.…”

mentioning

confidence: 99%

“…Such screening has not been performed when studying Aβ in the presence of detergent micelles. Instead, multiple detergents and conditions have been used, leading to diverse and contradictory results ranging from Aβ being monomeric and adopting an α-helical structure (13) to Aβ forming oligomers rich in β-sheet structure (14,15). Moreover, the links between the Aβ species formed in the presence of detergent micelles and those formed in lipid environments has not been established.…”

mentioning

confidence: 99%

Aβ42 assembles into specific β-barrel pore-forming oligomers in membrane-mimicking environments

Serra-Batiste

Ninot-Pedrosa

Bayoumi

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

242

318

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The formation of amyloid-β peptide (Aβ) oligomers at the cellular membrane is considered to be a crucial process underlying neurotoxicity in Alzheimer’s disease (AD). Therefore, it is critical to characterize the oligomers that form within a membrane environment. To contribute to this characterization, we have applied strategies widely used to examine the structure of membrane proteins to study the two major Aβ variants, Aβ40 and Aβ42. Accordingly, various types of detergent micelles were extensively screened to identify one that preserved the properties of Aβ in lipid environments—namely the formation of oligomers that function as pores. Remarkably, under the optimized detergent micelle conditions, Aβ40 and Aβ42 showed different behavior. Aβ40 aggregated into amyloid fibrils, whereas Aβ42 assembled into oligomers that inserted into lipid bilayers as well-defined pores and adopted a specific structure with characteristics of a β-barrel arrangement that we named β-barrel pore-forming Aβ42 oligomers (βPFOsAβ42). Because Aβ42, relative to Aβ40, has a more prominent role in AD, the higher propensity of Aβ42 to form βPFOs constitutes an indication of their relevance in AD. Moreover, because βPFOsAβ42 adopt a specific structure, this property offers an unprecedented opportunity for testing a hypothesis regarding the involvement of βPFOs and, more generally, membrane-associated Aβ oligomers in AD.

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Mamma Mia, P‐glycoprotein binds again

et al. 2020

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The levels of amyloid peptides in the brain are regulated by a clearance pathway from neurons to the blood-brain barrier. The first step is thought to involve diffusion from the plasma membrane to the interstitium. However, amyloid peptides are hydrophobic and avidly intercalate within membranes. The ABC transporter P-glycoprotein is implicated in the clearance of amyloid peptides across the blood-brain, but its role at neurons is undetermined. We here propose that P-glycoprotein mediates 'exit' of amyloid peptides from neurons. Indeed, amyloid peptides have physicochemical similarities to substrates of P-glycoprotein, but their larger size represents a conundrum. This review probes the plausibility of a mechanism for amyloid peptide transport by P-glycoprotein exploiting evolving biochemical and structural models.

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Alzheimer?s Disease: Soluble Oligomeric A?(1?40) Peptide in Membrane Mimic Environment from Solution NMR and Circular Dichroism Studies

Cited by 60 publications

References 33 publications

Conformational solution studies of the SDS micelle‐bound 11‐28 fragment of two Alzheimer's β‐amyloid variants (E22K and A21G) using CD, NMR, and MD techniques

Conformational solution studies of the SDS micelle‐bound 11‐28 fragment of two Alzheimer's β‐amyloid variants (E22K and A21G) using CD, NMR, and MD techniques

Aβ42 assembles into specific β-barrel pore-forming oligomers in membrane-mimicking environments

Mamma Mia, P‐glycoprotein binds again

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