A plant cell-based system that predicts aβ42 misfolding: Potential as a drug discovery tool for Alzheimer's disease

Zhao, Tianzhi; Zeng, Ying; Kermode, Allison R.

doi:10.1016/j.ymgme.2012.08.010

Cited by 15 publications

(11 citation statements)

References 50 publications

(71 reference statements)

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“…In Aβ‐GFP fusion protein, Aβ aggregates rapidly, resulting in misfolding of the fused GFP, thereby reducing the fluorescence intensity. The inhibition of Aβ aggregation may improve GFP folding, thus increasing the fluorescent signal in Aβ‐GFP‐expressing cells . Tet‐On Aβ‐GFP 293 cells were used to assess the effect of the test compounds on Aβ aggregation (Figure A).…”

Section: Resultsmentioning

confidence: 99%

Novel synthetic chalcone‐coumarin hybrid for Aβ aggregation reduction, antioxidation, and neuroprotection

et al. 2018

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Background Aggregation of misfolded amyloid β (Aβ) in senile plaques causes oxidative stress and neuronal death in Alzheimer's disease (AD). Compounds possessing antiaggregation and antioxidant properties are promising candidate compounds for AD treatment. Methods We examined the potential of synthetic derivatives of licochalcone A and coumarin for inhibiting Aβ aggregation, scavenging reactive oxygen species (ROS), and providing neuroprotection by using biochemical assays and Tet‐On Aβ‐GFP 293/SH‐SY5Y cell models for AD. Results Among test compounds, LM‐031, a novel chalcone‐coumarin hybrid, inhibited Aβ aggregation and scavenged free oxygen radicals. LM‐031 markedly reduced Aβ misfolding and ROS as well as promoted neurite outgrowth and inhibited acetylcholinesterase in Tet‐On Aβ‐GFP 293/SH‐SY5Y cells. Mechanistic studies showed upregulation of the HSPB1 chaperone, NRF2/NQO1/GCLC pathway, and CREB/BDNF/BCL2 pathway. Decreased neurite outgrowth upon the induction of Aβ‐GFP was rescued by LM‐031, which was counteracted by knockdown of HSPB1, NRF2, or CREB. Conclusion Taken together, these findings demonstrate that LM‐031 exhibited antiaggregation, antioxidant, and neuroprotective effects against Aβ toxicity by enhancing HSPB1 and the NRF2‐related antioxidant pathway as well as by activating the CREB‐dependent survival and antiapoptosis pathway. These results imply that LM‐031 may be a new therapeutic compound for AD.

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Section: Resultsmentioning

confidence: 99%

Novel synthetic chalcone‐coumarin hybrid for Aβ aggregation reduction, antioxidation, and neuroprotection

et al. 2018

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“…Chakrabortee et al, 2007), have been developed as tools to identify efficient inhibitors of polyglutamine protein aggregation. Zhao et al (2012) reported recently that the amyloid peptide A␤42 involved in the pathogenesis of Alzheimer's disease (AD) is capable of misfolding and subsequent aggregation within the plant cell environment, and suggested this model as a screening platform for AD drug discovery. In the EGFP-HttQ52 plant cell model that we describe, the polyphenolic compound EGCG not only suppresses polyQ aggregation, but also reduces the growth inhibitory effect of HttQ52 on BY-2 cells.…”

Section: Discussionmentioning

confidence: 99%

“…Nagai and Popiel, 2008). To investigate whether BY-2 cells expressing EGFPHttQ52 would be a useful model in this context, we tested the polyphenolic compound EGCG, which is known to reduce formation of amyloid and other protein aggregates (Ehrnhoefer et al, 2006;Zhao et al, 2012), using a small-scale version of the PCV method performed in 24-well culture plates. We first showed that the inhibitory effect of EGFP-HttQ52 on cell growth could be detected with this method over a 5 day incubation period (Fig.…”

Section: Tobacco Cells Expressing Egfp-httq52 As a Potential Screeninmentioning

confidence: 99%

A plant cell model of polyglutamine aggregation: Identification and characterisation of macromolecular and small-molecule anti-protein aggregation activity in vivo

Liu

Tunnacliffe

et al. 2015

Journal of Biotechnology

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“…These may be metabolites that are present in the wild-type plant or, if a mutation alters a relevant biosynthetic pathway, then “novel” active metabolites with enhanced activity at the target may be generated (Rogers et al 2003). Target proteins have previously been expressed in plant cells as screens (Littleton 2007, Doukhanina et al 2007, Zhao et al 2012, Gunjan et al 2013), but this is the first report in which survival of mutant plant cells expressing a foreign target protein has been used to direct secondary metabolism toward a specific pharmacological phenotype. Proof of concept uses Lobelia cardinalis , which contains lobinaline, a novel inhibitor of the human dopamine transporter (DAT) (Littleton et al 2004, Brown et al 2016).…”

Section: Introductionmentioning

confidence: 99%

Target-directed discovery and production of pharmaceuticals in transgenic mutant plant cells

Brown

Rogers

Gunjan

et al. 2016

Journal of Biotechnology

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Plants are a source of complex bioactive compounds, with value as pharmaceuticals, or leads for synthetic modification. Many of these secondary metabolites have evolved as defenses against competing organisms. and their pharmaceutical value is “accidental”, resulting from homology between target proteins in these competitors, and human molecular therapeutic targets. Here we show that it is possible to use mutation and selection of plant cells to re-direct their “evolution” toward metabolites that interact with the therapeutic target proteins themselves. This is achieved by expressing the human target protein in plant cells, and selecting mutants for survival based on the interaction of their metabolome with this target. This report describes the successful evolution of hairy root cultures of a Lobelia species toward increased biosynthesis of metabolites that inhibit the human dopamine transporter protein. Many of the resulting selected mutants are overproducing the active metabolite found in the wild-type plant, but others overproduce active metabolites that are not readily detectable in non-mutants. This technology can access the whole genomic capability of a plant species to biosynthesize metabolites with a specific target. It has potential value as a novel platform for plant drug discovery and production, or as a means of optimizing the therapeutic value of medicinal plant extracts.

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A plant cell-based system that predicts aβ42 misfolding: Potential as a drug discovery tool for Alzheimer's disease

Cited by 15 publications

References 50 publications

Novel synthetic chalcone‐coumarin hybrid for Aβ aggregation reduction, antioxidation, and neuroprotection

Novel synthetic chalcone‐coumarin hybrid for Aβ aggregation reduction, antioxidation, and neuroprotection

A plant cell model of polyglutamine aggregation: Identification and characterisation of macromolecular and small-molecule anti-protein aggregation activity in vivo

Target-directed discovery and production of pharmaceuticals in transgenic mutant plant cells

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