Requirement of aggregation propensity of Alzheimer amyloid peptides for neuronal cell surface binding

Bateman, David A.; McLaurin, JoAnne; Chakrabartty, Avijit

doi:10.1186/1471-2202-8-29

Cited by 32 publications

(31 citation statements)

References 72 publications

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“…The N-terminus of Aβ is solvent-exposed and therefore unlikely to be involved in the β-sheet formation which drives fibrillization [30], [31]. Also, work done in our laboratory and others indicates that various forms of N-terminally labeled Aβ40 behave similarly to unlabeled Aβ40 in terms of fibrillization [32], ability to permeabilize synthetic membranes [8], [29] as well as rat basophilic leukemia cell-derived membrane blebs (Figure S1), and toxicity to cultured cells [33]. The current studies were performed using Aβ40 labeled with HiLyte Fluor 647 by a C2-maleimide linkage at the N-terminus (termed HL647cAβ40).…”

Section: Resultsmentioning

confidence: 78%

Direct Observation of Single Amyloid-β(1-40) Oligomers on Live Cells: Binding and Growth at Physiological Concentrations

et al. 2011

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Understanding how amyloid-β peptide interacts with living cells on a molecular level is critical to development of targeted treatments for Alzheimer's disease. Evidence that oligomeric Aβ interacts with neuronal cell membranes has been provided, but the mechanism by which membrane binding occurs and the exact stoichiometry of the neurotoxic aggregates remain elusive. Physiologically relevant experimentation is hindered by the high Aβ concentrations required for most biochemical analyses, the metastable nature of Aβ aggregates, and the complex variety of Aβ species present under physiological conditions. Here we use single molecule microscopy to overcome these challenges, presenting direct optical evidence that small Aβ(1-40) oligomers bind to living neuroblastoma cells at physiological Aβ concentrations. Single particle fluorescence intensity measurements indicate that cell-bound Aβ species range in size from monomers to hexamers and greater, with the majority of bound oligomers falling in the dimer-to-tetramer range. Furthermore, while low-molecular weight oligomeric species do form in solution, the membrane-bound oligomer size distribution is shifted towards larger aggregates, indicating either that bound Aβ oligomers can rapidly increase in size or that these oligomers cluster at specific sites on the membrane. Calcium indicator studies demonstrate that small oligomer binding at physiological concentrations induces only mild, sporadic calcium leakage. These findings support the hypothesis that small oligomers are the primary Aβ species that interact with neurons at physiological concentrations.

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Section: Resultsmentioning

confidence: 78%

Direct Observation of Single Amyloid-β(1-40) Oligomers on Live Cells: Binding and Growth at Physiological Concentrations

et al. 2011

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“…It has previously been shown that Aβ (1-42) causes leaky peptide-lipid supramolecular structures, as a result of its membrane disrupting effect (Ambroggio et al, 2005). Indeed, the aggregation propensity of Aβ (1-42) was shown to be higher than that of Aβ (1-40) (Bateman et al, 2007). Consequently, it was demonstrated that the former peptide disrupts the membrane bilayer.…”

Section: Discussionmentioning

confidence: 99%

The interaction of amyloid Aβ(1–40) with lipid bilayers and ganglioside as studied by 31P solid-state NMR

Nakazawa

Suzuki

Williamson

et al. 2009

Chemistry and Physics of Lipids

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Amyloid β-peptide (Aβ) is a major component of plaques in Alzheimer's disease, and formation of senile plaques has been suggested to originate from regions of neuronal membrane rich in gangliosides. We analyzed the mode of interaction of Aβ with lipid bilayers by multinuclear NMR using 31 P nuclei. We found that Aβ (1-40) strongly perturbed the bilayer structure of dimyristoylphosphatidylcholine (DMPC), to form a non-lamellar phase (most likely micellar). The ganglioside GM1 potentiated the effect of Aβ (1-40), as viewed from 31 P NMR. The difference of the isotropic peak intensity between DMPC/Aβ and DMPC/GM1/Aβ suggests a specific interaction between Aβ and GM1. We show that in the DMPC/GM1/Aβ system there are three lipid phases, namely a lamellar phase, a hexagonal phase and non-oriented lipids. The latter two phases are induced by the presence of the Aβ peptide, and facilitated by GM1.Key Words: β-amyloid, Alzheimer's disease, NMR, GM1-ganglioside, lipid bilayer Abbreviations: DMPC: dimyristoylphosphatidylcholine, Aβ: Amyloid β-peptide, AD:Alzheimer's disease, NMR: Nuclear Magnetic Resonance 3 IntroductionAlzheimer's disease (AD) is a devastating neurodegenerative disease affecting up to 15 million individuals worldwide. The brains of Alzheimer's disease patients are characterized by fibrillar amyloid plaques that are associated with progressive deposits (Iversen et al., 1995). The principal component of amyloid deposits is a 39-42 amino acid residue peptide, Aβ (Glenner et al., 1984;Masters et al., 1985), a product of proteolytic processing of a much larger amyloid precursor protein encoded by a gene on chromosome 21 (Kang et al., 1987). Several spectroscopic investigations have clarified the structure of the fibrils, which form a 'cross-β sheet' structure (Kirschner et al., 1986;Petkova et al., 2002;Petkova et al., 2006). Moreover, a link between Aβ and AD neuropathological lesions is demonstrated by the toxicity of aggregated Aβ to neuronal cells in culture (Lambert et al., 1998) and in aged brain (Geula et al., 1998). However, the molecular mechanisms of the neurotoxic action of Aβ remain unknown. A growing number of observations indicate that Aβ may alter the physicochemical properties of neuronal membranes, including membrane fluidity (Muller et al., 1995) and permeability to ions and nonelectrolytes (Arispe et al., 1993;de Planque et al., 2007; Lau et al., 2006).These findings strongly suggest that at least some of the pathophysiological effects of Aβ may be mediated by Aβ-membrane interactions. Indeed, a number of studies have shown that Aβ is able to perturb lipid bilayers (Arispe et al., 1993). Interest in studies of the interaction between Aβ and constituents of brain membranes has been further stimulated by the identification of an Aβ-GM1 ganglioside-bound form in AD brain (Chi et al., 2007; Kakio et al., 2002;Yanagisawa et al., 1995). 4Gangliosides (Brocca et al., 1997; Kasahara et al., 2001) are sialic acid-containing glycosphingolipids and consist of two main components: a hydrophobic...

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“…12 Oligomers impair long-term potentiation events of hippocampal brain slices, 9,13 and it is theorized that their pathogenicity arises, at least in part, from the ability of Aβ peptide to interact with cellular membranes and to permeabilize these lipid bilayer structures. 11,14 Aβ peptide possesses amphiphilic properties, arising from the combination of a hydrophilic N-terminus, containing several charged residues, and a much more hydrophobic C-terminus ( Fig. 1a and b).…”

Section: Introductionmentioning

confidence: 97%

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

Dahse¹,

Garvey²,

Kovermann³

et al. 2010

Journal of Molecular Biology

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Requirement of aggregation propensity of Alzheimer amyloid peptides for neuronal cell surface binding

Abstract: Background: Aggregation of the amyloid peptides, Aβ40 and Aβ42, is known to be involved in the pathology of Alzheimer's disease (AD). Here we investigate the relationship between peptide aggregation and cell surface binding of three forms of Aβ (Aβ40, Aβ42, and an Aβ mutant).

Cited by 32 publications

References 72 publications

Direct Observation of Single Amyloid-β(1-40) Oligomers on Live Cells: Binding and Growth at Physiological Concentrations

Direct Observation of Single Amyloid-β(1-40) Oligomers on Live Cells: Binding and Growth at Physiological Concentrations

The interaction of amyloid Aβ(1–40) with lipid bilayers and ganglioside as studied by 31P solid-state NMR

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

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