Phosphodiesterase 1 (PDE1) has been demonstrated to be a potential drug target for a variety of diseases, ranging from peripheral system disease (PSD) to central nervous system disorders (CNSD). However, how cyclic nucleotide signaling, regulated by PDE1, particularly its isoform PDE1A, regulates the pathology of neurodegenerative disorders, including Alzheimer’s disease (AD), remains unclarified.

The Gene Expression Omnibus (GEO) database, a public gene expression repository, was used to analyze the role of PDE1 dysfunction in AD pathology. The mRNA and long non-coding RNA (lncRNA) were analyzed by comparing their differences in the GENCODE data resource V22. The relationship between PDE1, particularly PDE1A, and competing endogenous RNA (ceRNA) was validated by a dual-luciferase assay and reverse transcription-quantitative PCR (RT-qPCR), suggesting a potential ceRNA relationship among XIST, miR-338–3p, and PDE1A. Further cell-based assay and behavioral tests were conducted to determine the neuroprotective and memory-enhancing effects of PDE1 inhibition in cell and mouse models of AD.

A total of 11,781 differentially expressed genes (DEGs) were identified as AD- related genes. Approximately 1131 genes were identified as mitochondrial dysfunction-related by Venn plot analysis and were closely associated with AD pathology. PDE1, especially PDE1A, interacts with the lncRNA-microRNA network to promote cellular infiltration. These bioinformatic analyses were further supported by cell-based assays and behavioral studies, which demonstrated that treatment with the PDE1 inhibitor vinpocetine and PDE1A knockout ameliorated mitochondrial morphological abnormalities, restored immune function, and enhanced memory in a mouse model of AD.

These findings demonstrate that PDE1, particularly PDE1A activity, plays critical roles in AD progression by modulating mitochondrial morphology, immunity, and neuronal function, ultimately contributing to cognitive deficits.