Potential role of IP3/Ca2+ signaling and phosphodiesterases: Relevance to neurodegeneration in Alzheimer’s disease and possible therapeutic strategies

Despite large investments by industry and governments, no disease-modifying medications for the treatment of patients with Alzheimer's disease (AD) have been found. The failures of various clinical trials indicate the need for a more in-depth understanding of the pathophysiology of AD and for innovative therapeutic strategies for its treatment. Here, we review the rational for targeting IP3 signaling, cytosolic calcium dysregulation, phosphodiesterases (PDEs), and secondary messengers like cGMP and cAMP, as well as their correlations with the pathophysiology of AD. Various drugs targeting these signaling cascades are still in pre-clinical and clinical trials which support the ideas presented in this article. Further, we describe different molecular mechanisms and medications currently being used in various pre-clinical and clinical trials involving IP3/Ca+2 signaling. We also highlight various isoforms, as well as the functions and pharmacology of the PDEs broadly expressed in different parts of the brain and attempt to unravel the potential benefits of PDE inhibitors for use as novel medications to alleviate the pathogenesis of AD.