Synthesis of Aβ[1‐42] and its derivatives with improved efficiency

Zarándi, Márta; Soós, Katalin; Fülöp, Lívia; Bozsó, Zsolt; Datki, Zsolt; Tóth, Gábor; Penke, Botond

doi:10.1002/psc.801

Cited by 44 publications

(37 citation statements)

References 32 publications

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“…A␤1-42 was synthesized as described previously (Zarándi et al, 2007) by a solid-phase procedure involving Wang-resin and Fmoc chemistry. Crude peptide was purified on a C-4 RP-HPLC column; pure fractions were pooled and lyophilized.…”

Section: Preparation Of A␤1-42 and A␤25-35 Speciesmentioning

confidence: 99%

Amyloid β-Induced Neuronal Hyperexcitability Triggers Progressive Epilepsy

Minkeviciene¹,

Rheims²,

Dobszay³

et al. 2009

J. Neurosci.

573

544

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Alzheimer's disease is associated with an increased risk of unprovoked seizures. However, the underlying mechanisms of seizure induction remain elusive. Here, we performed video-EEG recordings in mice carrying mutant human APPswe and PS1dE9 genes (APdE9 mice) and their wild-type littermates to determine the prevalence of unprovoked seizures. In two recording episodes at the onset of amyloid ␤ (A␤) pathogenesis (3 and 4.5 months of age), at least one unprovoked seizure was detected in 65% of APdE9 mice, of which 46% had multiple seizures and 38% had a generalized seizure. None of the wild-type mice had seizures. In a subset of APdE9 mice, seizure phenotype was associated with a loss of calbindin-D28k immunoreactivity in dentate granular cells and ectopic expression of neuropeptide Y in mossy fibers. In APdE9 mice, persistently decreased resting membrane potential in neocortical layer 2/3 pyramidal cells and dentate granule cells underpinned increased network excitability as identified by patch-clamp electrophysiology. At stimulus strengths evoking single-component EPSPs in wild-type littermates, APdE9 mice exhibited decreased action potential threshold and burst firing of pyramidal cells. Bath application (1 h) of A␤1-42 or A␤25-35 (proto-)fibrils but not oligomers induced significant membrane depolarization of pyramidal cells and increased the activity of excitatory cell populations as measured by extracellular field recordings in the juvenile rodent brain, confirming the pathogenic significance of bath-applied A␤ (proto-)fibrils. Overall, these data identify fibrillar A␤ as a pathogenic entity powerfully altering neuronal membrane properties such that hyperexcitability of pyramidal cells culminates in epileptiform activity.

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Section: Preparation Of A␤1-42 and A␤25-35 Speciesmentioning

confidence: 99%

Amyloid β-Induced Neuronal Hyperexcitability Triggers Progressive Epilepsy

Minkeviciene¹,

Rheims²,

Dobszay³

et al. 2009

J. Neurosci.

573

544

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“…Peptides Aβ 1−40 and Aβ 1−42 were synthesized at the Department of Medical Chemistry, University of Szeged, as it was previously described [26,27]. Prior to measurements the purified peptide was dissolved in 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP; Sigma) and incubated overnight at room temparature in order to destroy the pre-formed aggregates.…”

Section: Peptidesmentioning

confidence: 99%

Protection of the Blood-Brain Barrier by Pentosan Against Amyloid-β-Induced Toxicity

Deli

Veszelka

Csiszár

et al. 2010

JAD

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Abstract. Endothelial cells of brain capillaries forming the blood-brain barrier play an important role in the pathogenesis and therapy of Alzheimer's disease. Amyloid-β (Aβ) peptides are key pathological elements in the development of the disease. A blood-brain barrier model, based on primary rat brain endothelial cells was used in which the barrier properties were induced by glial cells. The effects of amyloid peptides have been tested on cell viability and barrier functions. Aβ showed toxic effects on primary rat brain endothelial cells measured by MTT dye conversion and the lactate dehydrogenase release. Morphologically cytoplasmic vacuolization, disruption of the structure of cytoplasmic organelles and tight junctions could be observed in brain endothelial cells. Treatment with Aβ1−42 decreased the electrical resistance, and increased the permeability of brain endothelial cell monolayers for both fluorescein and albumin. Serum amyloid P component which stabilizes Aβ fibrils in cortical amyloid plaques and cerebrovascular amyloid deposits significantly potentiated the barrier-weakening effect of Aβ1−42. Sulfated polysaccharide pentosan could decrease the toxic effects of Aβ peptides in brain endothelial cells. It could also significantly protect the barrier integrity of monolayers from damaging actions of peptides. Pentosan modified the size, and significantly decreased the number of amyloid aggregates demonstrated by atomic force microscopy. The present data further support the toxic effects of amyloid peptides on brain endothelial cells, and can contribute to the development of molecules protecting the blood-brain barrier in Alzheimer's disease.

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“…Aβ1–42 (a gift from Márta Zarándi [32]) peptide was dissolved in 100% hexafluoro-isopropanol (HFIP) for 6 h to prepare a monomer solution [33]. The monomer solution was centrifuged at 15,000 g (10 min), and the supernatant was lyophilized and kept at –80°C until use.…”

Section: Methodsmentioning

confidence: 99%

Effects of Estrogen on Beta-Amyloid-Induced Cholinergic Cell Death in the Nucleus Basalis Magnocellularis

Szegő¹,

Csorba

Janáky

et al. 2010

Neuroendocrinology

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Alzheimer disease is characterized by accumulation of β-amyloid (Aβ) and cognitive dysfunctions linked to early loss of cholinergic neurons. As estrogen-based hormone replacement therapy has beneficial effects on cognition of demented patients, and it may prevent memory impairments, we investigated the effect of estrogen-pretreatment on Aβ-induced cholinergic neurodegeneration in the nucleus basalis magnocellularis (NBM). We tested which Aβ species induces the more pronounced cholinotoxic effect in vivo. We injected different Aβ assemblies in the NBM of mice, and measured cholinergic cell and cortical fiber loss. Spherical Aβ oligomers had the most toxic effect. Pretreatment of ovariectomized mice with estrogen before Aβ injection decreased cholinergic neuron loss and partly prevented fiber degeneration. By using proteomics, we searched for proteins involved in estrogen-mediated protection and in Aβ toxicity 24 h following injection. The change in expression of, e.g., DJ-1, NADH ubiquinone oxidoreductase, ATP synthase, phosphatidylethanolamine-binding protein 1, protein phosphatase 2A and dimethylarginine dimethylaminohydrolase 1 support our hypothesis that Aβ induces mitochondrial dysfunction, decreases MAPK signaling, and increases NOS activation in NBM. On the other hand, altered expression of, e.g., MAP kinase kinase 1 and 2, protein phosphatase 1 and 2A by Aβ might increase MAPK suppression and NOS signaling in the cortical target area. Estrogen pretreatment reversed most of the changes in the proteome in both areas. Our experiments suggest that regulation of the MAPK pathway, mitochondrial pH and NO production may all contribute to Aβ toxicity, and their regulation can be prevented partly by estrogen pretreatment.

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Synthesis of Aβ[1‐42] and its derivatives with improved efficiency

Cited by 44 publications

References 32 publications

Amyloid β-Induced Neuronal Hyperexcitability Triggers Progressive Epilepsy

Amyloid β-Induced Neuronal Hyperexcitability Triggers Progressive Epilepsy

Protection of the Blood-Brain Barrier by Pentosan Against Amyloid-β-Induced Toxicity

Effects of Estrogen on Beta-Amyloid-Induced Cholinergic Cell Death in the Nucleus Basalis Magnocellularis

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