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
oleh: Kazuma Murakami, Mayuko Yoshimura, Shota Nakagawa, Toshiaki Kume, Takayuki Kondo, Haruhisa Inoue, Kazuhiro Irie
| Format: | Article |
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| Diterbitkan: | MDPI AG 2020-02-01 |
Deskripsi
Amyloid <i>β</i>42 (Aβ42), a causative agent of Alzheimer’s disease (AD), is derived extracellularly from A<i>β</i> precursor protein (APP) following the latter’s cleavage by <i>β</i>-secretase, but not α-secretase. Protein kinase C<i>α</i> (PKC<i>α</i>) activation is known to increase <i>α</i>-secretase activity, thereby suppressing A<i>β</i> production. Since Aβ42 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, (<b>1</b>), which decreased Aβ42 in the conditioned medium of rat primary cerebral cortex cells. These results are associated with increased α-secretase but not PKC<i>ε</i>-dependent A<i>β</i>-degrading enzyme. The amount of neuronal embryonic lethal abnormal vision (nELAV), a known <i>β</i>-secretase stabilizer, was reduced by treatment with <b>1</b>. Notably, <b>1</b> prevented the formation of intracellular toxic oligomers. Furthermore, <b>1</b> suppressed toxic oligomerization within human iPS-derived neurons such as bryo-1. Given that <b>1</b> was not neurotoxic toward either cell line, these findings suggest that <b>1</b> is a potential drug lead for AD therapy.