From synapses to tangles: PDE inhibitors as therapeutic modulators in Alzheimer's disease

Alzheimer's disease (AD), historically characterized by amyloid plaques and tau tangles, is increasingly recognized as a disorder of intracellular signalling failure-where second messengers such as cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) become silent before memory does. These cyclic nucleotides are critical for synaptic plasticity, memory consolidation, and neurovascular function, operating through tightly regulated pathways involving protein kinases such as protein kinase A (PKA) and protein kinase G (PKG), transcription factors like cAMP response element-binding protein (CREB), and phosphodiesterases (PDEs). In the healthy brain, cAMP and cGMP orchestrate gene transcription, long-term potentiation, and cerebral blood flow. However, in AD, these signalling networks are progressively disrupted. Although it is not clear, whether failures in cyclic nucleotide signalling lead to amyloid beta and tau pathology or these pathological hallmarks disrupt the signalling mechanisms and lead to synaptic failure. However, the evidence suggests both of these possibilities. Amyloid-β oligomers and tau pathology impair adenylyl and guanylyl cyclase activity, reduce CREB phosphorylation, and disrupt nitric oxide (NO) signalling. Concurrently, overexpression of PDEs accelerates cyclic nucleotide degradation, silencing downstream pathways essential for neuronal resilience and plasticity. Dysregulated cyclic nucleotide signalling has been linked to neurovascular dysfunction, and cognitive decline. The present review is significant as it reframes AD as a signalling failure disorder rather than solely a protein aggregation disease. By identifying cyclic nucleotide dysregulation as a central and druggable mechanism, it establishes a strong translational rationale for targeting PDE-mediated degradation. This mechanism-driven perspective provides a focused platform for therapeutic innovation aimed at restoring synaptic integrity and improving cognitive outcomes in AD.