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

Amyloid 42 (Aβ42), a causative agent of Alzheimer's disease (AD), is derived extracellularly from A precursor protein (APP) following the latter's cleavage by -secretase, but not α-secretase. Protein kinase Cα (PKCα) activation is known to increase α-secretase activity, thereby suppressing A 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, (), which decreased Aβ42 in the conditioned medium of rat primary cerebral cortex cells. These results are associated with increased α-secretase but not PKC-dependent A-degrading enzyme. The amount of neuronal embryonic lethal abnormal vision (nELAV), a known -secretase stabilizer, was reduced by treatment with . Notably, prevented the formation of intracellular toxic oligomers. Furthermore, suppressed toxic oligomerization within human iPS-derived neurons such as bryo-1. Given that was not neurotoxic toward either cell line, these findings suggest that is a potential drug lead for AD therapy.