Inhibitors of Intracellular Signaling Molecules: New Horizons in Drug Discovery for the Treatment of Alzheimer's Disease

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Alzheimer's disease (AD) is a prime example of a pathology with extremely low treatment efficiency. The relevance of developing new drugs for its treatment is beyond doubt. Modern research in the discovery of therapeutic intervention in some neurodegenerative diseases indicates a high prospect of using intracellular signaling pathways as targets. We studied the effect of selective inhibitors of MEK1, p38α/p38β, NF-κB, JAKs, STAT3, adenylate cyclase, and PKA on the functioning of neural stem cells (NSC) and committed neuronal precursors (NCP) in an in vitro model of amyloid-β-induced neurodegeneration. The results of the experiments indicate the formation of fundamentally new patterns of intracellular signaling during the regulation of proliferation and specialization of progenitors under the influence of neurotoxic fragments of β-amyloid. There is a desynchronization of NSC and NCP activities. It was found that the pharmacological regulation of signal transduction in regeneration-competent cells (RCCs) with the help of selective inhibitors of some intracellular molecules leads to the coordination of the pro-regenerative capacity of different types of progenitors. The findings indicate the prospect for the discovery of new drugs with neuroregenerative activity for the treatment of AD based on inhibitors of MEK1, p38α/p38β, NF-кB, STAT3, and PKA. The obtained data expand the horizon of using modifiers of intracellular signaling molecule activity and open new prospects for targeted regulation of intracellular signaling.