Elongation of the C-terminal domain of an anti-amyloid β single-chain variable fragment increases its thermodynamic stability and decreases its aggregation tendency

Rivera-Hernández, Geovanny; Argany, Meysam; Blasco-Moreno, Bernat; Bonet, Jaume; Oliva, Baldomero; Villegas, Sandra

doi:10.4161/mabs.25382

Cited by 18 publications

(29 citation statements)

References 33 publications

(52 reference statements)

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“…50 This rational design, together with further constructs using these stabilized mutants, i.e., in the form of diabodies, could help to translate this antibody fragment into a therapeutic for treating humans.…”

Section: Discussionmentioning

confidence: 99%

Early intervention in the 3xTg-AD mice with an amyloid β-antibody fragment ameliorates first hallmarks of Alzheimer disease

Giménez-Llort

Rivera-Hernández

Argany

et al. 2013

mAbs

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The single-chain variable fragment, scFv-h3D6, has been shown to prevent in vitro toxicity induced by the amyloid β (Aβ) peptide in neuroblastoma cell cultures by withdrawing Aβ oligomers from the amyloid pathway. Present study examined the in vivo effects of scFv-h3D6 in the triple-transgenic 3xTg-AD mouse model of Alzheimer disease. Prior to the treatment, five-month-old female animals, corresponding to early stages of the disease, showed the first behavioral and psychological symptoms of dementia -like behaviors. Cognitive deficits included long- and short-term learning and memory deficits and high swimming navigation speed. After a single intraperitoneal dose of scFv-h3D6, the swimming speed was reversed to normal levels and the learning and memory deficits were ameliorated. Brain tissues of these animals revealed a global decrease of Aβ oligomers in the cortex and olfactory bulb after treatment, but this was not seen in the hippocampus and cerebellum. In the untreated 3xTg-AD animals, we observed an increase of both apoJ and apoE concentrations in the cortex, as well as an increase of apoE in the hippocampus. Treatment significantly recovered the non-pathological levels of these apolipoproteins. Our results suggest that the benefit of scFv-h3D6 occurs at both behavioral and molecular levels.

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Section: Discussionmentioning

confidence: 99%

Early intervention in the 3xTg-AD mice with an amyloid β-antibody fragment ameliorates first hallmarks of Alzheimer disease

Giménez-Llort

Rivera-Hernández

Argany

et al. 2013

mAbs

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“…24 Lipopolysaccharides (LPS), the major endotoxins of gram-negative bacteria, were removed from the protein by using Detoxi-Gel Endotoxin Removing columns (Thermo Scientific).…”

Section: Methodsmentioning

confidence: 99%

Loss of deep cerebellar nuclei neurons in the 3xTg-AD mice and protection by an anti-amyloid β antibody fragment

Esquerda-Canals¹,

Marti²,

Rivera-Hernández³

et al. 2013

mAbs

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Section: Discussionmentioning

confidence: 99%

“…This binding activity was retained for at least 1 month of storage at 4°C. The stability of phage-free NUsc1 is significant as scFvs are known to be prone to aggregation or cleavage at the flexible linker connecting the variable domains (Frenkel et al 2000;Worn and Pluckthun 2001;Rivera-Hernandez et al 2013;Cheng et al 2016). Free from the large bacteriophage, soluble scFvs may have greater utility than their phage-bound counterparts in experiments designed for high-resolution structural characterization of their targets.…”

Section: Discussionmentioning

confidence: 99%

A human scFv antibody that targets and neutralizes high molecular weight pathogenic amyloid‐β oligomers

Sebollela

Cline

Popova

et al. 2017

Journal of Neurochemistry

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Brain accumulation of soluble oligomers of the amyloid-β peptide (AβOs) is increasingly considered a key early event in the pathogenesis of Alzheimer's disease (AD). A variety of AβO species have been identified, both in vitro and in vivo, ranging from dimers to 24mers and higher order oligomers. However, there is no consensus in the literature regarding which AβO species are most germane to AD pathogenesis. Antibodies capable of specifically recognizing defined subpopulations of AβOs would be a valuable asset in the identification, isolation, and characterization of AD-relevant AβO species. Here, we report the characterization of a human single chain antibody fragment (scFv) denoted NUsc1, one of a number of scFvs we have identified that stringently distinguish AβOs from both monomeric and fibrillar Aβ. NUsc1 readily detected AβOs previously bound to dendrites in cultured hippocampal neurons. In addition, NUsc1 blocked AβO binding and reduced AβO-induced neuronal oxidative stress and tau hyperphosphorylation in cultured neurons. NUsc1 further distinguished brain extracts from AD-transgenic mice from wild type (WT) mice, and detected endogenous AβOs in fixed AD brain tissue and AD brain extracts. Biochemical analyses indicated that NUsc1 targets a subpopulation of AβOs with apparent molecular mass greater than 50 kDa. Results indicate that NUsc1 targets a particular AβO species relevant to AD pathogenesis, and suggest that NUsc1 may constitute an effective tool for AD diagnostics and therapeutics.

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Elongation of the C-terminal domain of an anti-amyloid β single-chain variable fragment increases its thermodynamic stability and decreases its aggregation tendency

Abstract: (2013) Elongation of the C-terminal domain of an anti-amyloid β single-chain variable fragment increases its thermodynamic stability and decreases its aggregation tendency, mAbs, 5:5, 678-689,

Cited by 18 publications

References 33 publications

Early intervention in the 3xTg-AD mice with an amyloid β-antibody fragment ameliorates first hallmarks of Alzheimer disease

Early intervention in the 3xTg-AD mice with an amyloid β-antibody fragment ameliorates first hallmarks of Alzheimer disease

Loss of deep cerebellar nuclei neurons in the 3xTg-AD mice and protection by an anti-amyloid β antibody fragment

A human scFv antibody that targets and neutralizes high molecular weight pathogenic amyloid‐β oligomers

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