Novel compound VB-037 inhibits Aβ aggregation and promotes neurite outgrowth through enhancement of HSP27 and reduction of P38 and JNK-mediated inflammation in cell models for Alzheimer's disease
| Autor: | Guey Jen Lee-Chen, Ying Chieh Sun, Yu Hsuan Hsieh, Ya Jen Chiu, Te Hsien Lin, Chiung Mei Chen, Kuo-Hsuan Chang, Guan Chiun Lee, Hsiu Mei Hsieh-Li |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Curcumin Neurite MAP Kinase Signaling System p38 mitogen-activated protein kinases Neuronal Outgrowth HSP27 Heat-Shock Proteins Caspase 1 Proto-Oncogene Mas p38 Mitogen-Activated Protein Kinases Neuroprotection Cell Line Mice Protein Aggregates 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Hsp27 Alzheimer Disease Heat shock protein Animals Humans Viability assay Protein kinase A Amyloid beta-Peptides biology Chemistry Cell Biology Cell biology 030104 developmental biology Quinolines biology.protein Inflammation Mediators 030217 neurology & neurosurgery |
| Zdroj: | Neurochemistry International. 125:175-186 |
| ISSN: | 0197-0186 |
| Popis: | The pathogenesis of Alzheimer's disease (AD) is involved in the aggregation of misfolded amyloid β (Aβ), which upregulates the activity of acetylcholinesterase (AChE), increases the production of reactive oxygen species (ROS), enhances neuroinflammation, and eventually leads to neuronal death. Therefore, compounds targeting these mechanisms may be candidates for multitarget drugs in AD treatment. We found that two quinoline derivatives, VB-030 and VB-037, markedly reduced Aβ aggregation and ROS levels in the thioflavin T biochemical assay and Tet-On Aβ-green fluorescent protein (GFP) 293 AD cell model. These compounds further improved neurite outgrowth, reduced AChE activity and upregulated the molecular chaperone heat shock protein family B [small] member 1 (HSP27), whereas knockdown of HSP27 counteracted the compounds' neuroprotective effects on the Tet-On Aβ-GFP SH-SY5Y AD neuronal model. Furthermore, VB-037 attenuated lipopolysaccharide (LPS)/interferon (IFN)-γ-induced activation of BV-2 microglial cells. In addition, VB-037 demonstrated its potential to diminish LPS/IFN-γ-induced upregulation of caspase 1 activity, expression of interleukin (IL)-1β, and active phosphorylation of mitogen-activated protein kinase 14 (P38), mitogen-activated protein kinase 8 (JNK), and Jun proto-oncogene, AP-1 transcription factor subunit (JUN) signalings, as well as improve cell viability in the Tet-On Aβ-GFP SH-SY5Y AD neuronal model. Our findings strongly indicate the potential of VB-037 for modifying AD progression by targeting multiple mechanisms, thereby offering a new drug development avenue for AD treatment. |
| Databáze: | OpenAIRE |
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