Inhibiting cAMP-pathways as a Potential Treatment Strategy for ’Alzheimer’s Disease

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. Promising is the creation of approaches to stimulate neurogenesis. As part of implementing this route, it is promising to search for targets among intracellular signaling molecules, including cAMP-dependent intracellular pathways. The work aimed to study the effect of adenylate cyclase (AC) and PKA inhibitors on the functions of regeneration-competent cells (neural progenitors and neuroglial cells of various types) in the conditions of modeling β-amyloid-induced neurodegeneration (βAIN) in vitro. The experiments were performed on C57B1/6 male mice. We studied the effect of the AC (2ʹ,5ʹ-Dideoxyadenosine and PKA inhibitors (2ʹ,5ʹ-Dideoxyadenosine and KT 5720) on the functioning of neural stem cells (NSC), neuronal committed progenitors (NCP), and neuroglial cells of the subventricular zone of the cerebral hemispheres (SVZ). Using immunomagnetic sorting, NCP and individual types of neuroglial cells were isolated from SVZ cells. We revealed the discoordination of the activity of NSC and NCP under the influence of neurotoxic β-amyloid. The ability of the AC and PKA inhibitors to synchronize the implementation of the functions of different types of progenitors under conditions of βAIN was found. The blockade of cAMP-dependent pathways upon exposure to a neurotoxic agent also led to an increase in the production of neurotrophic growth factors by several types of neuroglial cells. Particularly pronounced was the reaction of oligodendrocytes and microglial cells during PKA inactivation. The obtained results indicate the possibility of coordinated stimulation of the functions of different types of progenitors and neuroglial cells using selective inhibitors of intracellular molecules of cAMP-dependent pathways (primarily PKA) in AD.