Targeting of adenylate cyclase and protein kinase A: An advanced concept of Alzheimer’s disease pharmacotherapy

Objectives: The extremely low efficiency of existing methods of treating Alzheimer’s disease (AD) makes it highly relevant to develop fundamentally new drugs for its therapy. It is advisable to create drugs that stimulate neurodegeneration. As part of the implementation of this route, it is promising for the identification of targets from numerous intracellular signalling molecules, including Cyclic adenosine monophosphate (cAMP)-dependent intracellular pathways. The work objective was to explore the potential of regulating the brain regeneration-competent cells (progenitors and neurogliacytes of various types) using the adenylate cyclase and protein kinase A blockers under conditions of the neurotoxic effects of beta-amyloid in vitro . Materials and Methods: The C57BL/6 mice were used. The functioning of neural stem cells (NSCs), neuronal committed progenitor (NCP) cells and neurogliocytes of the subventricular zone of the brain under the influence of blockers of adenylate cyclase (Chemical Abstracts Service [CAS] number 6698-26-6) and protein kinase A (CAS 108068-98-0) was studied. NCP, astrocytes, oligodendrocytes and microgliacytes were obtained from neural tissue using immunomagnetic sorting. Results: We revealed the discoordination of the activity of NSC and NCP under the action of neurotoxic b-amyloid. The ability of the adenylate cyclase and protein kinase A blockers to synchronise the implementation of the progenitors’ functions when exposed to beta-amyloid was found. The blockade of cAMP-dependent pathways on exposure to a neurotoxic agent also enhanced the secretion of stimulatory neural progenitors by several types of neurogliocytes. Particularly pronounced was the reaction of oligodendrocytes and microglial cells during protein kinase A inactivation. Conclusion: The results show the potential of coordinated stimulation of the functions of different progenitors and neurogliocytes using selective inhibitors of intracellular molecules of cAMP-dependent pathways (primarily protein kinase A) in Alzheimer’s dementia.