Title:Insight into JNK Inhibition-based Strategy for the Treatment of
Alzheimer's Disease
Volume: 20
Issue: 1
Author(s): Gleb Nikolaevich Zyuz’kov*, Larisa Arkad`evna Miroshnichenko, Tatyana Yur`evna Polykova, Elena Vladislavovna Simanina, Alexander Vasil`evich Chayikovskyi and Larisa Yur`evna Kotlovskaya
Affiliation:
- Goldberg Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Center,
Russian Academy of Sciences, Tomsk, Russia
Keywords:
Alzheimer's disease, neural stem cells, β-amyloid, JNK inhibitors, protein kinases, intracellular signaling pathways.
Abstract:
Background: Existing drugs for the treatment of Alzheimer's disease do not meet the basic
requirements. Therefore, it is necessary to search for fundamentally new targets for the discovery of
drugs for Alzheimer's disease (AD). When creating approaches to stimulate neurogenesis, such a search
is promising to conduct as part of the development of a strategy for targeted regulation of intracellular
signal transduction in regeneration-competent cells (RCCs). Moreover, the participation of c-Jun Nterminal
kinases (JNK) in the regulation of the functions of the nervous tissue and neuroglial cells is
known.
Objective: The aim of the work was to study the effect of the JNK inhibitor (IQ-1S) on exploratory behavior
and cognitive functions in aged mice (16-month-old male C57BL/6 mice as a model of AD) in
combination with the dynamics of shifts in the RCCs functioning (nervous tissue progenitors: neural
stem cells (NSCs) and neuronal-committed progenitors (NCPs); neuroglial cells: astrocytes, oligodendrocytes,
microglial cells).
Methods: The studies were carried out on male C57BL/6 mice aged 16 months as model of Alzheimer's
disease. We studied the effect of the JNK inhibitor on exploratory behavior, conditioned reflex activity,
and on the functioning of RCCs in the subventricular zone of the cerebral hemispheres (SVZ). NCPs
and neuroglial cells of different types were obtained by immunomagnetic separation.
Results: We observed significant changes in exploratory behavior and impaired conditioned reflex activity
in aged C57BL/6 mice. The administration of the JNK inhibitor led to a significant correction of
age-related behavioral and memory disorders in aged mice. At the same time, against the background of
JNK inhibition-based therapy, an increase in mitotic activity and the content of both NSCs and NCPs in
the SVZ was noted. However, these shifts were more pronounced in committed precursors. The phenomenon
of the inhibition of NSC specialization under the influence of a pharmacological agent was
also revealed. In addition, the JNK inhibitor caused an increase in the secretion of neurotrophic growth
factors by oligodendrocytes and microglial cells.
Conclusion: The findings open up prospects for the development of JNK targeting-based approaches
for the treatment of AD.
