Alteration of the JNK signaling pathway in the hippocampus associated with age and development of AD-like pathology, and impact of IQ-1S

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Abstract

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder that is the leading cause of senile dementia. Age is a key risk factor for the most common (>95%) sporadic form of AD; there are no effective methods for its prevention or treatment. Growing evidence indicates that the development of AD and other neurodegenerative diseases is associated with activation of mitogen-activated protein kinase pathways, and the JNK signaling pathway is considered a potential target for the prevention and treatment of AD, although information on changes in its activity during ontogenesis is extremely limited. The aim of this study was to compare age-related changes in the activity of the JNK signaling pathway in the hippocampus of Wistar rats and OXYS rats, which spontaneously develop all the key features of AD, and to evaluate the effect of a selective JNK3 inhibitor [sodium salt of 11H-indeno[1,2-b]quinoxalin-11-one oxime (IQ-1S)]. The ability of IQ-1S to suppress accelerated aging of the OXYS rat brain has been proven previously, but its effect on JNK activity has not been studied. In the present study, we showed that with age, the activity of the JNK signaling pathway increases in the hippocampus of rats of both lines. At the same time, the manifestation and active progression of AD signs in OXYS rats occur against the background of increased, compared to Wistar rats, phosphorylation of the key kinase of this signaling pathway – JNK3 and its target proteins, which allows us to consider JNK3 as a potential target for interventions aimed at preventing neurodegenerative processes. This is also supported by the fact that the neuroprotective effect of the selective JNK3 inhibitor IQ-1S, which we previously identified, and its ability to suppress the development of neurodegenerative processes in OXYS rats, is associated with a decrease in the level of phosphorylation of JNK3, c-Jun, APP and Tau in the hippocampus.

About the authors

N. A. Muraleva

Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences

Author for correspondence.
Email: Myraleva@bionet.nsc.ru
Russian Federation, 630090 Novosibirsk

A. A. Zhdankina

Siberian State Medical University

Email: Myraleva@bionet.nsc.ru
Russian Federation, 634050 Tomsk

A. I. Khlebnikov

Tomsk Polytechnic University

Email: Myraleva@bionet.nsc.ru

Kizhner Research Center

Russian Federation, 634050 Tomsk

N. G. Kolosova

Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences

Email: Myraleva@bionet.nsc.ru
Russian Federation, 630090 Novosibirsk

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