Inhibiting β-Secretase Activity in Alzheimer's Disease Cell Models with Single-Chain Antibodies Specifically Targeting APP

Boddapati, Shanta; Levites, Yona; Sierks, Michael R.

doi:10.1016/j.jmb.2010.10.054

Cited by 33 publications

(21 citation statements)

References 50 publications

(55 reference statements)

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“…With its important physiological activity, it also separates many other substrates. Panning process suggested ScFv, since it forbids the activity of BACE-1 toward APP by means of binding the APP substrate at the proteolytic site (42). The panning results were verified by ELISA in this study.…”

Section: Discussionsupporting

confidence: 64%

Specific Single Chain Antibodies Against A Neuronal Growth Inhibitor Receptor, Nogo Receptor 1: Promising New Antibodies for the Immunotherapy of Multiple Sclerosis

Ehsaei¹,

Nejatollahi²,

Mohammadi³

2017

Shiraz E-Med J

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Background: The Nogo-66 receptor (NgR1) is a myelin inhibitory neuronal receptor in Multiple Sclerosis (MS) and is a crucial key to axonal growth inhibition. The NgR1 inhibition role has been proved by monoclonal antibodies in many researches. Human single chain antibodies are composed of VH-linker-VL. They are tiny but powerful antibodies which have remarkable effects on treatments. Objectives: Producing specific single-chain antibodies of human against immune-dominant epitope of NgR1 and the evaluation of their reactivity against the epitope is the main goal of this study. Methods: An immunodominant epitope of NgR1 was designed using bioinformatics methods. The peptide was applied to select specific single chain antibodies using a phage antibody display library of scFv (single chain Fragment variable) and panning process. The selected clones were PCR (Polymerase Chain Reaction) amplified and DNA fingerprinted, to reveal the common patterns. Phage ELISA was performed to evaluate the reactivity of the selected scFvs. Results: Two specific clones with the frequencies of 55% and 45% were detached. Positive ELISA were detected with the corresponding epitope for clones, but for negative controls no positive reaction took place. The corresponding peptide-coated wells for scFv 1 and scFv 2 absorbed 0.81 and 0.62, respectively, which were significantly higher than the absorbance of the wells without any peptide, ie, 0.10 and 0.14, respectively. Conclusions: Using monoclonal antibody in the case of targeted therapy against NgR1 prevents Nogo-A, myelin associated glycoprotein, and oligodendrocyte from binding to Ngr1 and disturbs demyelination. Results demonstrated the selection of two specific scFvs against NgR1 which reacted with the antigen significantly. These specific, small human antibodies can be considered as blockings for Multiple Sclerosis to interfere with the axonal growth inhibition in NgR1-expressing neurons. Further studies should be conducted to find the effects of these antibodies in vitro and in vivo.

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Section: Discussionsupporting

confidence: 64%

Specific Single Chain Antibodies Against A Neuronal Growth Inhibitor Receptor, Nogo Receptor 1: Promising New Antibodies for the Immunotherapy of Multiple Sclerosis

Ehsaei¹,

Nejatollahi²,

Mohammadi³

2017

Shiraz E-Med J

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“…An agent that can bind to the β-cleavage site of APP may inhibit the production of Aβ without the potential adverse effects of BACE1 inhibition. Similar approaches were demonstrated with a monoclonal antibody and protein that bind to the β-cleavage site of APP [37]–[39]. As of yet, only a few β-site-directed antibodies and few peptide have been reported to improve cognitive function and reduce neuropathology in vivo [37], [38], [40], [41].…”

Section: Introductionmentioning

confidence: 70%

“…To accomplish this goal, agents binding to the BACE1 cleavage site in the APP substrate instead of the enzyme are main candidates. To our knowledge, few agents that bound to the β-site of APP and reduced Aβ production in vitro has been reported [39]. Here, we present a peptide, S1, which binds to both β-site of APP and Aβ N-terminal, significantly reduces APP cleavage and decreases Aβ production in vitro and in vivo .…”

Section: Discussionmentioning

confidence: 95%

A Peptide Binding to the β-Site of APP Improves Spatial Memory and Attenuates Aβ Burden in Alzheimer’s Disease Transgenic Mice

et al. 2012

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Amyloid precursor protein cleaving enzyme 1 (BACE1), an aspartyl protease, initiates processing of the amyloid precursor protein (APP) into β-amyloid (Aβ); the peptide likely contributes to development of Alzheimer’s disease (AD). BACE1 is an attractive therapeutic target for AD treatment, but it exhibits other physiological activities and has many other substrates besides APP. Thus, inhibition of BACE1 function may cause adverse side effects. Here, we present a peptide, S1, isolated from a peptide library that selectively inhibits BACE1 hydrolytic activity by binding to the β-proteolytic site on APP and Aβ N-terminal. The S1 peptide significantly reduced Aβ levels in vitro and in vivo and inhibited Aβ cytotoxicity in SH-SY5Y cells. When applied to APPswe/PS1dE9 double transgenic mice by intracerebroventricular injection, S1 significantly improved the spatial memory as determined by the Morris Water Maze, and also attenuated their Aβ burden. These results indicate that the dual-functional peptide S1 may have therapeutic potential for AD by both reducing Aβ generation and inhibiting Aβ cytotoxicity.

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“…The authors successfully screened for scFvs specifically binding and hence blocking BACE1's APP processing site. Although these scFvs are not in clinical use yet, it is a good example of direct translation of research performed in yeast into clinically relevant approaches (Boddapati et al, 2011). Furthermore, Yeast Two Hybrid is an excellent method to study protein-protein interaction on a large scale in vivo.…”

Section: Budding Yeast Models To Study Effects Of Aβ and Defects In Pmentioning

confidence: 99%

Yeast buddies helping to unravel the complexity of neurodegenerative disorders

Fruhmann

Seynnaeve

Zheng

et al. 2017

Mechanisms of Ageing and Development

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Inhibiting β-Secretase Activity in Alzheimer's Disease Cell Models with Single-Chain Antibodies Specifically Targeting APP

Cited by 33 publications

References 50 publications

Specific Single Chain Antibodies Against A Neuronal Growth Inhibitor Receptor, Nogo Receptor 1: Promising New Antibodies for the Immunotherapy of Multiple Sclerosis

Specific Single Chain Antibodies Against A Neuronal Growth Inhibitor Receptor, Nogo Receptor 1: Promising New Antibodies for the Immunotherapy of Multiple Sclerosis

A Peptide Binding to the β-Site of APP Improves Spatial Memory and Attenuates Aβ Burden in Alzheimer’s Disease Transgenic Mice

Yeast buddies helping to unravel the complexity of neurodegenerative disorders

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