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Article

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

1
Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan
2
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan
3
Department of Applied Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan
4
Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan
5
iPSC-based Drug Discovery and Development Team, RIKEN BioResource Research Center (BRC), Kyoto 619-0237, Japan
6
Medical-risk Avoidance based on iPS Cells Team, RIKEN Center for Advanced Intelligence Project (AIP), Kyoto 606-8507, Japan
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(4), 1179; https://doi.org/10.3390/ijms21041179
Received: 15 January 2020 / Revised: 31 January 2020 / Accepted: 6 February 2020 / Published: 11 February 2020
Amyloid β42 (Aβ42), a causative agent of Alzheimer’s disease (AD), is derived extracellularly from Aβ precursor protein (APP) following the latter’s cleavage by β-secretase, but not α-secretase. Protein kinase Cα (PKCα) activation is known to increase α-secretase activity, thereby suppressing Aβ 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, (1), which decreased Aβ42 in the conditioned medium of rat primary cerebral cortex cells. These results are associated with increased α-secretase but not PKCε-dependent Aβ-degrading enzyme. The amount of neuronal embryonic lethal abnormal vision (nELAV), a known β-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. View Full-Text
Keywords: alzheimer’s disease; amyloid β; bryostatin-1; ECE1; iPS; nELAV; neurotoxicity; oligomer; protein kinase C; α-secretase alzheimer’s disease; amyloid β; bryostatin-1; ECE1; iPS; nELAV; neurotoxicity; oligomer; protein kinase C; α-secretase
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MDPI and ACS Style

Murakami, K.; Yoshimura, M.; Nakagawa, S.; Kume, T.; Kondo, T.; Inoue, H.; Irie, K. 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. Int. J. Mol. Sci. 2020, 21, 1179. https://doi.org/10.3390/ijms21041179

AMA Style

Murakami K, Yoshimura M, Nakagawa S, Kume T, Kondo T, Inoue H, Irie K. 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. International Journal of Molecular Sciences. 2020; 21(4):1179. https://doi.org/10.3390/ijms21041179

Chicago/Turabian Style

Murakami, Kazuma, Mayuko Yoshimura, Shota Nakagawa, Toshiaki Kume, Takayuki Kondo, Haruhisa Inoue, and Kazuhiro Irie. 2020. "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" International Journal of Molecular Sciences 21, no. 4: 1179. https://doi.org/10.3390/ijms21041179

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