Stereospecific interactions are necessary for Alzheimer disease amyloid-β toxicity

Ciccotosto, Giuseppe D.; Tew, Deborah J.; Drew, Simon C.; Smith, D.G.; Johanssen, Timothy; Lal, Varsha; Lau, Tong-Lay; Perez, Keyla; Curtain, Cyril C.; Wade, John D.; Separovic, Frances; Masters, Colin L.; Smith, Jeffrey P.; Barnham, Kevin J.; Cappai, Roberto

doi:10.1016/j.neurobiolaging.2009.02.018

Cited by 51 publications

(68 citation statements)

References 52 publications

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“…MD modeling (Davis and Berkowitz 2009a,b) suggests the induction of subtle changes in conformation around the b-turn of Ab fold on its membrane binding, and in vitro studies show the effect of pH and the protonation of His13 and/or His14 when the amphiphilic domain Ab 11-22 is used for membrane binding studies (Ravault et al 2009). Using Land D-handed enantiomers of Ab 42, Ciccotosto et al (2011) have reported that synthetic Ab binds directly to cell membranes in vivo through phosphatidylserine and that this interaction is stereospecific. The toxicity of Ab oligomers may therefore be related in part to some aspect of its specific electrostatic interactions with phosphatidylserine.…”

Section: Electrostatic/charge Effectsmentioning

confidence: 99%

Biochemistry of Amyloid -Protein and Amyloid Deposits in Alzheimer Disease

Masters

Selkoe²

2012

Cold Spring Harbor Perspectives in Medicine

492

405

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Section: Electrostatic/charge Effectsmentioning

confidence: 99%

Biochemistry of Amyloid -Protein and Amyloid Deposits in Alzheimer Disease

Masters

Selkoe²

2012

Cold Spring Harbor Perspectives in Medicine

492

405

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“…Primary cortical neuronal cultures derived from C57BL/6 mice were prepared as described previously (Martinowich et al, 2003;Ciccotosto et al, 2009). Cells were seeded onto poly-D-lysine coated 6-well plates at 4 million cells per well and maintained in a humidified 37°C incubator Ͻ5% CO 2 .…”

Section: Methodsmentioning

confidence: 99%

Alleviating Transcriptional Inhibition of the NorepinephrineSlc6a2Transporter Gene in Depolarized Neurons

Kaipananickal¹,

Bayles²,

Ciccotosto³

et al. 2010

J. Neurosci.

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Recent studies have brought to light additional experimental information, namely, that the MeCP2 protein complex is not only capable of associating with members of the ATPase-dependent bromodomain family, but also found on nonmethylated genomic sequences. These unexpected results are indicative of a multifunctional role for MeCP2, more importantly; our view of the molecular mechanisms that regulate gene activity may not be necessarily distinguishable. Depolarized mouse neuronal cortical cells were examined for increased Slc6a2 mRNA synthesis, changes in CpG methylation status using bisulfite sequencing, and binding of MeCP2 and Smarca2 on the Slc6a2 promoter sequence by chromatin immunopurification strategies. Increased Slc6a2 gene expression in response to membrane depolarization was strongly correlated with the dissociation of MeCP2 and Smarca2 complex on the unmethylated gene. We identified that gene expression in neuronal cortical cells involves increased histone hyperacetylation on the Slc6a2 promoter, which is commensurate with the recruitment of SP1 and RNA Polymerase II and is inversely correlated with H3K9 trimethylation. We hypothesize that the MeCP2 corepressor is capable of associating with multiple forms of SWI/SNF to remodel chromatin for important regulatory roles. The results of our experiments indicate that these proteins are asymmetrically bound to chromatin independent of DNA methylation and not inevitably diametrically opposed. These results now begin to offer a new perspective on the mechanism of Slc6a2 gene regulation.

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“…4). Since Ab neurotoxicity is associated with neuronal cell binding, 11,16,17 we examined whether the non-toxic nature of pAb42 may be due to an altered cell binding characteristic. This experiment was performed using F 430 -Ab42(S26C) and F 430 -pAb42(S26C) labelled peptides at a subtoxic concentration (5 mM).…”

Section: Toxicity and Cell Binding Properties Of Phosphorylated Ab42mentioning

confidence: 99%

“…The ability of Ab to bind lipids and form amyloid plaques indicates that its interaction with neuronal membranes is a key event for its aggregation into toxic species to induce neurotoxicity. [10][11][12] Thus, it is important to understand whether posttranslational modifications of Ab can modulate its interaction with lipid membranes, lead to the peptide acquiring cytotoxic properties and cause cell death. Since phospholipids and cholesterol are the main components of membranes, 13 the interactions of Ab peptide with membrane lipids and lipid mimetic compounds were studied.…”

Section: Introductionmentioning

confidence: 99%

Phosphorylation of a full length amyloid-β peptide modulates its amyloid aggregation, cell binding and neurotoxic properties

et al. 2017

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Amyloid beta peptide (Ab) is the major protein component of the amyloid plaques that are present in the brains of Alzheimer's disease (AD) patients. Ab42 peptide is a known neurotoxic agent that binds to neurons and, under specific aggregation conditions, triggers cell death. Ab peptide can undergo specific amino acid posttranslational modifications, such as phosphorylation, that are important for modulating its proteolytic degradation, aggregation, binding to lipid membranes and neurotoxic functions. Peptides phosphorylated at serine 8 in full-length Ab42 (pAb42) were synthesised and compared to native Ab42 peptide. Their secondary structures, aggregation properties and interactions with plasma membranes of primary cortical neurons were investigated. The results revealed that pAb42 has increased b-sheet formation with rapid amyloid formation in a synthetic lipid environment, which was associated with increased cellular binding but concomitant diminished neurotoxicity. Our data support the notion that phosphorylation of Ab42 promotes the formation of amyloid plaques in the brain, which lack the neurotoxic properties associated with oligomeric species causing pathogenesis in AD.

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Stereospecific interactions are necessary for Alzheimer disease amyloid-β toxicity

Cited by 51 publications

References 52 publications

Biochemistry of Amyloid -Protein and Amyloid Deposits in Alzheimer Disease

Biochemistry of Amyloid -Protein and Amyloid Deposits in Alzheimer Disease

Alleviating Transcriptional Inhibition of the NorepinephrineSlc6a2Transporter Gene in Depolarized Neurons

Phosphorylation of a full length amyloid-β peptide modulates its amyloid aggregation, cell binding and neurotoxic properties

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