DHPC Strongly Affects the Structure and Oligomerization Propensity of Alzheimer's Aβ(1–40) Peptide

Dahse, Kirsten; Garvey, Megan; Kovermann, Michael; Vogel, Alexander; Balbach, Jochen; Fändrich, Marcus; Fahr, Alfred

doi:10.1016/j.jmb.2010.09.021

Cited by 32 publications

(25 citation statements)

References 92 publications

(116 reference statements)

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“…This suggests that peptide binding to DHPC micelles induces β-sheet formation by Aβ. Direct peptide interactions with DHPC micelles were confi rmed in surface tension and proton NMR studies (Dahse et al 2010 ). Fluorescence studies using diagnostic dye 1-anilino-8-naphthalene sulfonate suggested that the Aβ interactions with individual lipid molecules and with micelles have a hydrophobic component.…”

Section: Interactions Of Aβ With Lipid Molecules and Surfaces: A Testmentioning

confidence: 91%

“…In our study, the effects of DHPC on the structure and self-association properties of Aβ(1-40) were analyzed as a function of DHPC concentration by using a wide range of biophysical techniques (Dahse et al 2010 ). The results showed that DHPC promoted Aβ aggregation at concentrations well below and above its CMC.…”

Section: Interactions Of Aβ With Lipid Molecules and Surfaces: A Testmentioning

confidence: 95%

“…In contrast, other studies showed signifi cant effects of PCs on the secondary structure and aggregation of Aβ; this includes our own work described in Sect. 3.4.3 below (Dahse et al 2010 ). Such a diversity in the results reported in different studies illustrates extreme sensitivity of the Aβ solution conformation not only to the presence of specifi c lipids but also to many other factors, such as the solvent composition, ionic strength, pH, and lipid to peptide ratio, to name a few (Matsuzaki 2007 ;Garvey et al 2011 ).…”

Section: Interactions Of Aβ With Lipids Surfaces: Electrostatic Effectsmentioning

confidence: 98%

“…These interactions differentially affect the secondary structure and aggregation properties of Aβ and accelerate both nucleation and growth of Aβ fi brils. These results imply that subtle peptide-lipid interactions involving zwitterionic phospholipids can greatly infl uence the overall aggregation properties of Aβ, as well as alter specifi c steps in the complex pathway of its fi brillogenesis (Dahse et al 2010 ).…”

Section: Interactions Of Aβ With Lipid Molecules and Surfaces: A Testmentioning

confidence: 99%

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Lipids in Amyloid-β Processing, Aggregation, and Toxicity

Morgado

Garvey

2015

Advances in Experimental Medicine and Biology

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Aggregation of amyloid-beta (Aβ) peptide is the major event underlying neuronal damage in Alzheimer's disease (AD). Specific lipids and their homeostasis play important roles in this and other neurodegenerative disorders. The complex interplay between the lipids and the generation, clearance or deposition of Aβ has been intensively investigated and is reviewed in this chapter. Membrane lipids can have an important influence on the biogenesis of Aβ from its precursor protein. In particular, increased cholesterol in the plasma membrane augments Aβ generation and shows a strong positive correlation with AD progression. Furthermore, apolipoprotein E, which transports cholesterol in the cerebrospinal fluid and is known to interact with Aβ or compete with it for the lipoprotein receptor binding, significantly influences Aβ clearance in an isoform-specific manner and is the major genetic risk factor for AD. Aβ is an amphiphilic peptide that interacts with various lipids, proteins and their assemblies, which can lead to variation in Aβ aggregation in vitro and in vivo. Upon interaction with the lipid raft components, such as cholesterol, gangliosides and phospholipids, Aβ can aggregate on the cell membrane and thereby disrupt it, perhaps by forming channel-like pores. This leads to perturbed cellular calcium homeostasis, suggesting that Aβ-lipid interactions at the cell membrane probably trigger the neurotoxic cascade in AD. Here, we overview the roles of specific lipids, lipid assemblies and apolipoprotein E in Aβ processing, clearance and aggregation, and discuss the contribution of these factors to the neurotoxicity in AD.

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Section: Interactions Of Aβ With Lipid Molecules and Surfaces: A Testmentioning

confidence: 91%

Section: Interactions Of Aβ With Lipid Molecules and Surfaces: A Testmentioning

confidence: 95%

Section: Interactions Of Aβ With Lipids Surfaces: Electrostatic Effectsmentioning

confidence: 98%

Section: Interactions Of Aβ With Lipid Molecules and Surfaces: A Testmentioning

confidence: 99%

See 2 more Smart Citations

Lipids in Amyloid-β Processing, Aggregation, and Toxicity

Morgado

Garvey

2015

Advances in Experimental Medicine and Biology

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“…Both effects have been shown to be important for the membrane interaction of these peptides. [16,18,20,27,28] Furthermore, the cross-interaction of IAPP and Ab in the presence of this membrane system was analyzed.To gain a detailed picture of the membrane-mediated aggregation process of IAPP, Ab, and their 1:1 mixture at the molecular level, both infrared spectroscopic and X-ray scattering techniques were applied. Monolayers of the lipid system were spread at the air-water interface and timedependent changes in the vertical and lateral structure and in the packing properties of the membrane were analyzed by synchrotron X-ray reflectivity (XRR), grazing incidence Xray diffraction (GIXD), and surface tensiometry.…”

mentioning

confidence: 99%

Cross‐Amyloid Interaction of Aβ and IAPP at Lipid Membranes

Seeliger¹,

Evers²,

Jeworrek³

et al. 2011

Angew Chem Int Ed

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Several proteins and peptides are known to form cytotoxic oligomers and amyloid fibrils-mainly consisting of intermolecular cross-b-sheets-upon misfolding and self-association.[1] As these amyloid aggregates deposit in tissues, they are associated with cell degenerative diseases, such as type-2 diabetes mellitus (T2DM) or Alzheimer's disease (AD).[1]The present study is focused on the membrane-mediated aggregation of heteroassemblies of the islet amyloid polypeptide (IAPP) and the b-amyloid (Ab) peptide. The extracellular deposits in the pancreas of patients with T2DM are mainly composed of the 37-residue IAPP, which is produced, stored, and secreted together with insulin by bcells in the pancreatic islets of Langerhans. [2,3] The major component of the extracellular plaques in AD brains is Ab, a 40-or 42-residue fragment of the membrane-associated amyloid precursor protein. [4,5] Recent clinical studies have pointed to a correlation between T2DM and AD, that is, patients with T2DM have a higher risk to suffer from AD and vice versa.[6] Remarkably, the sequences of IAPP and Ab show a 25 % identity and 50 % similarity and it has been shown that fibrillation of IAPP can be cross-seeded by Ab fibrils (Figure 1). [7] Most importantly, recent studies in vitro in the bulk phase have shown that early nonfibrillar and nontoxic Ab and IAPP species bind each other with high affinity forming soluble, nonfibrillar, and nontoxic heterooligomers and that this interaction delays the cytotoxic selfassociation and amyloidogenesis of both Ab and IAPP. [8] In this context, it has also been shown that the IAPP analogue [(N-Me)G24, (N-Me)I26]-IAPP or IAPP-GI, a mimic of nonamyloidogenic IAPP, forms nonfibrillar and nontoxic heteroassemblies with Ab and thus blocks the cytotoxic oligomer and fibril formation by Ab. [8,[12][13][14] As Ab and IAPP are present in blood and cerebrospinal fluid at similar concentrations, an in vivo interaction might be possible, which could be a molecular link between AD and T2DM. [9][10][11] Several studies have shown that lipid-peptide interactions can play a crucial role in amyloid formation of both IAPP and Ab, [1,3,[15][16][17][18][19][20][21][22][23][24][25][26][27][28] and the enhancement of fibrillation in the presence of membranes is believed to be causatively linked to the cellular damage caused by Ab or IAPP assemblies. [25,26,28] Here, the interaction of IAPP and Ab with a complex heterogeneous (raft-like) model biomembrane system comprising 15 % DOPC, 10 % DOPG, 40 % DPPC, 10 % DPPG, and 25 % cholesterol has been studied. This lipid system allows for addressing effects of lateral heterogeneity (i.e., coexisting liquid-disordered and liquid-ordered domains) as well as charge effects upon peptide-membrane interactions. Both effects have been shown to be important for the membrane interaction of these peptides. [16,18,20,27,28] Furthermore, the cross-interaction of IAPP and Ab in the presence of this membrane system was analyzed.To gain a detailed picture of the membrane-mediated aggregation proc...

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