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

Esquerda-Canals, Gisela; Marti, Joaquim; Rivera-Hernández, Geovanny; Giménez-Llort, Lydia; Villegas, Sandra

doi:10.4161/mabs.25428

Cited by 27 publications

(28 citation statements)

References 22 publications

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“…Therefore, these results demonstrate that scFv-h3D6-Pp shows the same therapeutic benefits, or slightly better, as those already known for scFv-h3D6 obtained from E . coli [ 26 , 27 ]. It is capable of withdrawing Aβ oligomers from the amyloid pathway and, this way, prevent their cytotoxicity.…”

Section: Resultsmentioning

confidence: 99%

“…After a single intraperitoneal dose of scFv-h3D6, learning and memory deficits were ameliorated and a global decrease in Aβ oligomers was observed in the cortex and the olfactory bulb of young 3xTg-AD females. Indeed, scFv-h3D6 showed a great potential for treating other molecular features of AD, as the recovering of the non-pathological levels of apolipoproteins E and J [ 26 , 27 ]. However, the expression of scFv-h3D6 in Escherichia coli , and especially its purification is an overwhelming process.…”

Section: Introductionmentioning

confidence: 99%

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Production of an anti-Aβ antibody fragment in Pichia pastoris and in vitro and in vivo validation of its therapeutic effect

et al. 2017

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ScFv-h3D6 has been shown as an efficient therapy in the 3xTg-AD mouse model of Alzheimer’s Disease. Because one of the major bottlenecks for the therapeutic uses of proteins produced in Escherichia coli is their potential contamination with endotoxins, LPS were extensively removed by a rather low-efficient, expensive, and time-consuming purification step. In addition, disulfide scrambling is favored in the reducing bacterial cytoplasm albeit the use of reductase deficient strains. To overcome these hurdles, as well as to improve the yield, the yeast Pichia pastoris, an endotoxin-free host system for recombinant protein production, has been used to produce scFv-h3D6, both in flask and in a fed-batch bioreactor. Comparison of the thermal stability of the obtained protein with that from E. coli showed no differences. Opposite to the case of the protein obtained from E. coli, no disulfide scrambled conformations or LPS traces were detected in that produced in P. pastoris. Cytotoxicity assays in SH-SY5Y neuroblastoma cell-cultures demonstrated that proteins from both expression systems were similarly efficient in precluding Aβ-induced toxicity. Finally, the 3xTg-AD mouse model was used to test the therapeutic effect of both proteins. Quantification of Aβ levels from cortex and hippocampus protein extracts by ELISA, and Aβ-immunohistochemistry, showed that both proteins reduced Aβ burden. This work demonstrates that scFv-h3D6 obtained from P. pastoris shows the same benefits as those already known for that obtained from E. coli, with multiple advantages in terms of recombinant production and safety.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Production of an anti-Aβ antibody fragment in Pichia pastoris and in vitro and in vivo validation of its therapeutic effect

et al. 2017

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“…MRI and MRS sessions were performed 5 days post‐administration ( N = 4 each group) at 5, 7, 9, and 12 months of age. This interval was chosen because our previous studies with this mouse model showed an evident effect 5 days after a single i.p dose of scFv‐h3D6 was administered to 5‐month‐old mice, as assessed by motor/behavioral/cognitive testing, histology, and molecular determinations (for 5 months, for 6 months). This demonstrates the huge capability of scFv‐h3D6 to reduce Aβ burden and so to protect neurons from death.…”

Section: Methodsmentioning

confidence: 99%

“…At the molecular level, scFv reduced Aβ oligomers and reverted the apolipoprotein E and J concentrations to their normal levels. At the cellular level, protection from neuronal loss has been described in the cerebellum and, more importantly, in the hippocampus and amygdala, while neither astrogliosis nor microgliosis were induced . Apart from being safe in terms of neuroinflammation, the treatment resulted safe in terms of kidneys and liver function, while the spleen could be involved in the clearance mechanism of the Aβ/scFv‐h3D6 complex …”

Section: Introductionmentioning

confidence: 99%

Progression of Alzheimer's disease and effect of scFv‐h3D6 immunotherapy in the 3xTg‐AD mouse model: An in vivo longitudinal study using Magnetic Resonance Imaging and Spectroscopy

et al. 2020

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Alzheimer's disease (AD) is an incurable disease that affects most of the 47 million people estimated as living with dementia worldwide. The main histopathological hallmarks of AD are extracellular β-amyloid (Aβ) plaques and intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein.In recent years, Aβ-immunotherapy has been revealed as a potential tool in AD treatment. One strategy consists of using single-chain variable fragments (scFvs), which avoids the fragment crystallizable (Fc) effects that are supposed to trigger a microglial response, leading to microhemorrhages and vasogenic edemas, as evidenced in clinical trials with bapineuzumab. The scFv-h3D6 generated by our research group derives from this monoclonal antibody, which targets the N-terminal of the Aβ peptide and recognizes monomers, oligomers and fibrils.In this study, 3xTg-AD mice were intraperitoneally and monthly treated with 100 μg of scFv-h3D6 (a dose of~3.3 mg/kg) or PBS, from 5 to 12 months of age (−mo), the age at which the mice were sacrificed and samples collected for histological and biochemical analyses. During treatments, four monitoring sessions using magnetic resonance imaging and spectroscopy (MRI/MRS) were performed at 5, 7, 9, and 12 months of age. MRI/MRS techniques are widely used in both human and mouse research, allowing to draw an in vivo picture of concrete aspects of the pathology in a non-invasive manner and allowing to monitor its development across time.Compared with the genetic background, 3xTg-AD mice presented a smaller volume in almost all cerebral regions and ages examined, an increase in both the intra and extracellular Aβ 1-42 at 12-mo, and an inflammation process at this age, in both the hippocampus (IL-6 and mIns) and cortex (IL-6). In addition, treatment with scFv-h3D6 partially recovered the values in brain volume, and Aβ, IL-6, and mIns concentrations, among others, encouraging further studies with this antibody fragment.Abbreviations: 3xTg-AD, triple-transgenic mouse model of AD.; 6E10+, mAb-6E10 immunoreactive

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“…scFv-h3D6 (Universitat Autonoma de Barcelona) is a recombinant single-chain variable antibody fragment and a derivative of bapineuzumab [667][668][669][670] (Thomson Reuters Pharma, update of October 28, 2013).…”

Section: Antibodies Against Amyloid-βmentioning

confidence: 99%

Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes. Disease-Modifying Drugs. Update 2014

Froestl

Pfeifer

Muhs

2014

JAD

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Scientists working in the field of Alzheimer's disease and, in particular, cognitive enhancers, are very productive. The review "Drugs interacting with Targets other than Receptors or Enzymes. Disease-modifying Drugs" was accepted in October 2012. In the last 20 months, new targets for the potential treatment of Alzheimer's disease were identified. Enormous progress was realized in the pharmacological characterization of natural products with cognitive enhancing properties. This review covers the evolution of research in this field through May 2014.

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

Cited by 27 publications

References 22 publications

Production of an anti-Aβ antibody fragment in Pichia pastoris and in vitro and in vivo validation of its therapeutic effect

Production of an anti-Aβ antibody fragment in Pichia pastoris and in vitro and in vivo validation of its therapeutic effect

Progression of Alzheimer's disease and effect of scFv‐h3D6 immunotherapy in the 3xTg‐AD mouse model: An in vivo longitudinal study using Magnetic Resonance Imaging and Spectroscopy

Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes. Disease-Modifying Drugs. Update 2014

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