Dual PDE4/10 Inhibition Restores CREB1 Function and Enhances Neuronal Resilience in Alzheimer's Disease

Background Alzheimer’s disease (AD) involves cognitive decline, amyloid-beta (Aβ) accumulation, tau hyperphosphorylation, and neuroinflammation. CREB1, a key transcription factor for memory, is downregulated in AD, contributing to disease progression. Methods We used human iPSC-derived cortical neurons and microglia, along with the APP/PS1 AD mouse model, to investigate the role of CREB1 and assess the therapeutic potential of dual PDE4/10 inhibition. Results CREB1 deficiency increased Aβ and p-tau231 accumulation. Dual inhibition of PDE4 and PDE10 activated the cAMP-PKA-CREB pathway, restoring CREB1 activity, reducing Aβ and p-tau231, and mitigating neuroinflammation. This intervention improved synaptic plasticity and cognitive performance in vivo. Conclusions Our findings demonstrate that dual PDE4/10 inhibition synergistically enhances CREB1 signaling, promoting neuroprotection and synaptic remodeling. This approach offers a promising therapeutic strategy for modifying AD pathology and restoring cognitive function.