Prospect of Using ERK1/2 and р38 in Regeneration-Competent Cells of Nervous Tissue as a Drug Targets for Treating Alzheimer’s Disease

Abstract

Drugs used to treat Alzheimer's disease (AD) were developed taking into account the existing classic hypotheses of its pathogenesis (cholinergic, amyloid, and tau-protein pathological changes). However, these pharmaceuticals have shown rather low efficacy in clinical practice. Therefore, it is relevant to develop approaches for controlling neurogenesis in AD, primarily by synchronizing the activities of different cell compartments of the cellular renewal system of nerve tissue. The search for a solution to this problem is promising in the framework of the "Strategy for targeted pharmacological regulation of intracellular signal transduction in regeneration-competent cells." In this work, we studied the effects of the ERK1/2 and p38 inhibitors on nervous tissue progenitors and neuroglial cells' functioning under the conditions of modeling β-amyloid-induced neurodegeneration in vitro. We identified opposing changes in proliferation and differentiation of neural stem cells (NSCs) and neuronal-committed progenitors (NCPs) influenced by β-amyloid (Aβ). It was also found that different types of neuroglia cells' secretion of neurotrophic growth factors (astrocytes, oligodendrocytes, and microglia), when exposed to Aβ, differ in vector. The ERK1/2 and p38 inhibitors' ability to coordinate the functions of regeneration-competent cells of different types has been discovered. Under their influence, synchronization of pro-regenerative activity of NSCs, NCPs, as well as oligodendrocytes and microglial cells under conditions of β-amyloid-induced neurodegeneration was revealed. The results show the prospect of developing novel drugs to treat AD with ERK1/2 and p38 inhibitors.