Cyclic nucleotide phosphodiesterase 1 and cognitive impairment: Mechanistic insights and therapeutic implications

Cognitive impairment is a defining feature of neurodegenerative diseases such as Alzheimer's disease (AD) and vascular dementia (VaD). However, the pathogenesis of cognitive impairment remains unclear, mainly because it involves complex pathological processes in which multiple cytokines and pathways contribute to its progression. Among key molecular regulators, cyclic nucleotide phosphodiesterase 1 (PDE1), a Calcium/calmodulin (Ca²⁺/CaM) activated enzyme that regulates intracellular levels of cAMP and cGMP by degrading them to inactive forms. PDE1 may play a critical role in influencing cognitive function through modulating these second messengers. PDE1 integrates calcium fluctuations with cyclic nucleotide metabolism, affecting a series of events including synaptic plasticity, neuronal survival, vascular tone, and neuroinflammatory responses. This review summarizes the distribution of PDE1 and its isoforms, and their regulatory mechanisms and functional roles, particularly those of PDE1A, PDE1B, and PDE1C, in the central nervous system (CNS) disorders. We also discussed the involvement of PDE1 in modulating cAMP/PKA and cGMP/PKG signaling pathways, and its impact on oxidative stress, neuroinflammation, and apoptotic cascades associated with cognitive dysfunction. In addition, this review integrates current evidence on PDE1 isoforms in both neuronal and vascular regulation of cognition, emphasizing their dual neurovascular roles in cognitive impairment. We further summarized recent progress on PDE1 target validation and the reported efficacy of PDE1A inhibitors in alleviating memory deficits associated with neurodegenerative disorders, such as AD and VaD.