ArticleAlzheimer's research & therapy2025
Dual PDE4/10A inhibition restores CREB1 function and enhances neuronal resilience in models of alzheimer's disease.
Article in Alzheimer's research & therapy, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed.
- PPARγ Signaling in the Central Nervous System: A Review of the Implications in Synaptic Plasticity, Neuroinflammatory and Neoplastic Processes.Neurochemical research · 2026Review
- Cancer therapy-related cognitive impairment, part 1: an integrative clinical-mechanistic framework from phenotypes to convergent neurobiological pathways.Pharmacological reports : PR · 2026Review
- Cancer therapy-related cognitive impairment, part 2: from bench to bedside-and back: why candidate therapies for cancer therapy-related cognitive impairment fail to translate.Pharmacological reports : PR · 2026Review
- Repurposing apremilast for alzheimer's disease: multitarget modulation of cAMP‑PI3K/Akt-GSK‑3β and NF‑κB signaling.Metabolic brain disease · 2026Review
- Targeting of neuroinflammation, oxidative stress, and synaptic dysfunction by vinpocetine in alzheimer's disease: a comprehensive appraisal.Metabolic brain disease · 2026Review
- The transcriptional and cellular landscape of cognitive resilience to Alzheimer's disease.Frontiers in molecular neuroscience · 2025Review
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14 authors.
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Abstract
backgroundAlzheimer'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. Phosphodiesterases 4 and 10 (PDE4 and PDE10) are key enzymes that degrade cAMP, a second messenger involved in CREB signaling, synaptic plasticity, and neuroprotection. Dysregulation of PDE activity has been implicated in AD and other neurodegenerative disorders.
methodsWe used human iPSC-derived cortical neurons and microglia, along with the APP/PS1 mouse model, to investigate the role of CREB1 and assess the therapeutic potential of dual PDE4/10A inhibition in AD.
resultsCREB1 deficiency in neurons increased Aβ and p-tau231 accumulation. Dual inhibition of PDE4 and PDE10A 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.
conclusionsOur findings demonstrate that dual PDE4/10A inhibition synergistically enhances the cAMP-PKA-CREB signaling, promoting neuroprotection and synaptic remodeling. This approach offers a promising therapeutic strategy for modifying AD pathology and restoring cognitive function.
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