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

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. be more complex, given the recent discovery of APP proteolysis by ηand δ-secretases, for example, in [3]. The ability of Aβ42 to aggregate and exhibit neurotoxicity is higher than that of Aβ40 despite the lower in vivo amounts of Aβ42 [4]. Aβ42 oligomer formation causes synaptic dysfunction and neuronal death in AD pathology, whereas the contribution of end-stage mature fibrils of Aβ42 to AD is lower than that of oligomers [5]. Higher-order toxic oligomers that show potent synaptotoxicity and neurotoxicity have been reported, such as protofibrils (PFs), Aβ-derived diffusible ligands, and amylospheroids [6]. Therefore, suppressing toxic oligomerization of Aβ42 is a favorable strategy for developing AD therapies. This suppression can also be achieved by simultaneously decreasing Aβ production while inducing Aβ degradation.Protein kinase C (PKC) is a family of serine/threonine kinases that plays a pivotal role in various biological events such as signal transduction, proliferation, and apoptosis mediated by the second messenger 1,2-diacyl-sn-glycerol [7]. The PKC family, which contains at least 10 isozymes, is divided into three groups, namely conventional (α, βI, βII, and γ), novel (δ, ε, η, and θ), and atypical (µ, ξ, and ι) [7]. PKC activity is related to memory formation and learning [8], while PKC downregulation may induce cognitive impairment and memory loss in AD [9]. Regarding Aβ-driven molecular events, PKCα reportedly upregulates α-secretase activity either directly or indirectly through the mitogen-activated protein kinase (MAPK) pathway [10]. PKCα activation in a mouse model of AD has beneficial effects on AD pathology, including the disruption of Aβ production and reduction of toxi...

Protein Kinase C Involvement in Neuroprotective Effects of Thymol and Carvacrol Against Toxicity Induced by Amyloid-β in Rat Hippocampal Neurons

“…PKCα belongs to the serine/threonine kinases family, and its signal transduction is mediated by calcium and diacylglycerol as second messengers ( Newton, 2010 ). It has been demonstrated that the activation of PKCα could elevate α-secretase activity that inhibits Aβ production ( Murakami et al, 2020 ). In the present study, we also observed that PKCα expression level is significantly increased in the thymol and carvacrol groups compared to Aβ.…”

Amyloid-β: Structure, Function, and Pathophysiological Significance in Neurodegenerative Diseases

“…This Special Issue also includes papers that addressed the preventive and/or therapeutic potentials of chemical compounds or drugs for Aβ-related neurodegenerative diseases. Murakami et al, who focused on 10-Me-Aplog-1, a new protein kinase C activator, demonstrated its inhibitory effects on the intracellular formation of toxic Aβ oligomers in rat primary cerebral cortex cells [ 7 ]. In a mouse model of cerebral amyloid angiopathy, Yakushiji et al showed that the administration of low-dose phosphodiesterase III inhibitor cilostazol improved vascular deposition of Aβ, potentially by facilitating perivascular drainage of Aβ [ 8 ].…”