Evaluation of Toxic Amyloid β42 Oligomers in Rat Primary Cerebral Cortex Cells and Human iPS-derived Neurons Treated with 10-Me-Aplog-1, a New PKC Activator
| Autor: | Toshiaki Kume, Shota Nakagawa, Kazuma Murakami, Kazuhiro Irie, Mayuko Yoshimura, Takayuki Kondo, Haruhisa Inoue |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
oligomer
lcsh:Chemistry neurotoxicity lcsh:QH301-705.5 Spectroscopy Cells Cultured protein kinase c Cerebral Cortex Neurons Chemistry ips alzheimer’s disease General Medicine Computer Science Applications Cell biology medicine.anatomical_structure Cerebral cortex amyloid β α-secretase Intracellular Protein Kinase C-alpha Bryostatin 1 Enzyme Activators nelav Catalysis Article Inorganic Chemistry ece1 Alzheimer Disease mental disorders medicine Animals Humans Physical and Theoretical Chemistry Rats Wistar Protein kinase A Molecular Biology Protein kinase C Amyloid beta-Peptides Activator (genetics) Organic Chemistry Neurotoxicity medicine.disease Peptide Fragments bryostatin-1 Rats lcsh:Biology (General) lcsh:QD1-999 Cell culture Amyloid Precursor Protein Secretases |
| Zdroj: | International Journal of Molecular Sciences, Vol 21, Iss 4, p 1179 (2020) International Journal of Molecular Sciences Volume 21 Issue 4 |
| ISSN: | 1422-0067 |
| Popis: | Amyloid &beta 42 (A&beta 42), a causative agent of Alzheimer&rsquo s disease (AD), is derived extracellularly from A&beta precursor protein (APP) following the latter&rsquo s cleavage by &beta secretase, but not &alpha secretase. Protein kinase C&alpha (PKC&alpha ) activation is known to increase &alpha secretase activity, thereby suppressing A&beta production. Since A&beta 42 oligomer formation causes potent neurotoxicity, APP modulation by PKC ligands is a promising strategy for AD treatment. Although bryostatin-1 (bryo-1) is a leading compound for this strategy, its limited natural availability and the difficulty of its total synthesis impedes further research. To address this limitation, Irie and colleagues have developed a new PKC activator with few side effects, 10-Me-Aplog-1, (1), which decreased A&beta 42 in the conditioned medium of rat primary cerebral cortex cells. These results are associated with increased &alpha secretase but not PKC&epsilon dependent A&beta degrading enzyme. The amount of neuronal embryonic lethal abnormal vision (nELAV), a known &beta secretase stabilizer, was reduced by treatment with 1. Notably, 1 prevented the formation of intracellular toxic oligomers. Furthermore, 1 suppressed toxic oligomerization within human iPS-derived neurons such as bryo-1. Given that 1 was not neurotoxic toward either cell line, these findings suggest that 1 is a potential drug lead for AD therapy. |
| Databáze: | OpenAIRE |
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