*Article* **Evaluation of Toxic Amyloid** β**42 Oligomers in Rat Primary Cerebral Cortex Cells and Human iPS-derived Neurons Treated with 10-Me-Aplog-1, a New PKC Activator**

**Kazuma Murakami 1,\* , Mayuko Yoshimura 1, Shota Nakagawa 2, Toshiaki Kume 2,3, Takayuki Kondo 4,5,6, Haruhisa Inoue 4,5,6 and Kazuhiro Irie 1,\***


Received: 15 January 2020; Accepted: 6 February 2020; Published: 11 February 2020

**Abstract:** 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.

**Keywords:** alzheimer's disease; amyloid β; bryostatin-1; ECE1; iPS; nELAV; neurotoxicity; oligomer; protein kinase C; α-secretase
