JNK Signaling Pathway Activity Alterations in the Rat Hippocampus: Effect of Age, Alzheimer’s Disease-Like Pathology Development, and the JNK Inhibitor IQ-1S

Abstract: Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder and the leading cause of senile dementia. The key risk factor for a more common (>95% of cases) sporadic form of AD is age. So far, there are no effective methods for AD prevention or treatment. A growing body of evidence indicates that the development of AD and other neurodegenerative diseases is associated with the activation of mitogen-activated protein kinase (MAPK) pathways, and JNK signaling pathway is considered as a potential target for the prevention and treatment of AD. However, the information on alterations in its activity in ontogenesis, which are evaluated by changes in the phosphorylation of its components, is extremely limited. The aim of this study was to compare age-related changes in the activity of JNK signaling pathway in the hippocampus of Wistar rats and senescence-accelerated OXYS rats (which spontaneously develop the key symptoms of AD-like pathology) and to evaluate the effect of the selective JNK3 inhibitor IQ-1S (11H-indeno[1,2-b]quinoxalin-11-one oxime sodium salt). The ability of IQ-1S to suppress accelerated brain aging in OXYS rat has been proven previously, but the effect of this inhibitor on the JNK activity has not been studied. Here, we showed that with age, the activity of the JNK signaling pathway increased in the hippocampus of rats of both strains. At the same time, the manifestation and active progression of AD-like pathology in OXYS rats was accompanied by the increase in the phosphorylation level of the key kinase of this signaling pathway, JNK3, and its target proteins compared to Wistar rats, which allowed us to suggest JNK3 as a potential target for interventions aimed at preventing neurodegenerative processes. This suggestion was supported by the fact that the neuroprotective effect of the selective JNK3 inhibitor IQ-1S and its ability to suppress the development of neurodegenerative processes in OXYS rats were associated with a decrease in the phosphorylation levels of JNK3, c-Jun, APP, and Tau in the hippocampus. © Pleiades Publishing, Ltd. 2025.