cAMP, cGMP and Amyloid β: Three Ideal Partners for Memory Formation

cAMP and cGMP are well established second messengers required for long-term potentiation (LTP) and memory formation/consolidation. By contrast, amyloid β (Aβ), mostly known as one of the main culprits for Alzheimer’s disease (AD), has received relatively little attention in the context of plasticity and memory. Of note, however, low physiological concentrations of Aβ seem necessary for LTP induction and for memory formation. This should come as no surprise, since hormesis emerged as a central dogma in biology. Additionally, recent evidence indicates that Aβ is one of the downstream effectors for cAMP and cGMP to trigger synaptic plasticity and memory. We argue that these emerging findings depict a new scenario that should change the general view on the amyloidogenic pathway, and that could have significant implications for the understanding of AD and its pharmacological treatment in the future. Past studies on the neurobiological basis of memory formation and consolidation led to the identification of LTP and its molecular determinants. Because the cAMP and cGMP signalosomes are involved in the different phases of LTP – phases that are correlated with short- and long-term memory – elevating the concentration of these two cyclic nucleotides by PDE inhibitors might provide a therapeutic strategy for treating memory deficiencies, for instance those seen in pathologies such as AD. These treatment approaches are currently under clinical evaluation. Consistent evidence demonstrates that Aβ, a peptide typically associated with AD as one of the main culprits of the disease, has in fact important physiological functions. In particular, it plays a critical role in LTP expression and memory consolidation, where it seems to act as a common effector of cAMP/cGMP signaling. In order to understand the pathophysiology of AD, we should acquire more detailed knowledge about the neurobiological functions of Aβ in the healthy brain.