Therapeutic potential of phosphodiesterase inhibitors for cognitive amelioration in Alzheimer's disease

Alzheimer's disease (AD), one of the greatest threats to human health, is characterized by declined cognition and changed behavior. Cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) that play an important role in learning and memory are hydrolyzed by phosphodiesterases (PDEs). Most PDE isoforms are highly expressed in the brain, and the inhibition of PDEs is beneficial to counteract AD. Thus, targeting PDEs represents a therapeutic potential for this disease. So far, a variety of PDE inhibitors have been discovered with significant cognitive enhancement effects in animal models and more than ten agents have entered into clinical trials. In this review, we summarize PDE mediated cyclic nucleotide signaling pathways, PDE family members involved in AD and recent advance of PDE inhibitors in preclinical and clinical studies, trying to provide an outlook of PDE inhibitors for the treatment of AD in future.