Phosphodiesterase 11A4 (PDE11A4)

Phosphodiesterase 11A4 (PDE11A4) is a dual-specificity enzyme responsible for the hydrolysis of the second messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) [NIH, 2024]. It is the longest isoform of the PDE11A family and is the only isoform expressed in the brain, where it is highly restricted to the hippocampal formation and hypothalamus [Frontiers, 2021; NIH, 2023]. PDE11A4 plays a crucial role in regulating synaptic plasticity, social memory consolidation, and mood stabilization [NIH, 2022]. Research indicates that PDE11A4 expression increases with age, leading to the formation of pathological protein aggregates called "ghost axons" that contribute to age-related cognitive decline and neuroinflammation [NIH, 2022; Frontiers, 2021]. Consequently, PDE11A4 has emerged as a promising therapeutic target for treating age-related memory disorders, dementia, and Alzheimer's disease [ACS, 2023]. Pharmacological strategies focus on selective inhibition of its catalytic activity or disruption of its homodimerization to restore cyclic nucleotide signaling [UM Ventures, 2025]. While the PDE5 inhibitor tadalafil exhibits weak cross-reactivity with PDE11A, current drug discovery efforts are focused on developing highly selective, brain-penetrant small molecules to minimize off-target effects on other PDE families [NIH, 2024; ACS, 2023].

Other names

PDE11APhosphodiesterase 11APDE11A isoform 4Dual 3',5'-cyclic nucleotide phosphodiesterase 11A

Inhibition of cAMP and cGMP hydrolysis, leading to elevated cyclic nucleotide levels and restoration of synaptic plasticity [NIH, 2024; UM Ventures, 2025].