Recent development in PDE4D-targeted inhibitors for Alzheimer's disease therapy

Alzheimer's disease (AD) is a complex neurodegenerative disorder primarily characterized by cognitive decline and memory impairment. Due to its elusive etiology, complex pathogenesis, and significant interindividual heterogeneity, current clinical interventions face substantial challenges. Therefore, exploring novel therapeutic targets and strategies remains a critical research focus. Phosphodiesterase-4 (PDE4), which specifically hydrolyzes cAMP, has shown potential as a therapeutic target for neurological disorders. However, the lack of subtype selectivity of existing PDE4 inhibitors often leads to dose-limiting adverse effects such as nausea and vomiting, compromising patient tolerance and hindering clinical translation. PDE4D, a key subtype of PDE4, is abundantly expressed in brain regions critical for cognitive function and is particularly involved in memory formation and learning processes. Recent studies indicate that selective inhibition of PDE4D can effectively circumvent these side effects. Consequently, PDE4D has emerged as a promising potential target in AD therapeutic research. This review aims to critically evaluate the regulatory role of PDE4D in neurodegeneration, assess its potential as a novel therapeutic target for AD, and discuss recent advances in the development of PDE4D inhibitors.