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Background <p>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. 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.</p> Methods <p>We 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&#xa0;in AD.</p> Results <p>CREB1 deficiency&#xa0;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.</p> Conclusions <p>Our 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.</p>

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Dual PDE4/10A inhibition restores CREB1 function and enhances neuronal resilience in models of alzheimer's disease

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月27日

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  • Xiaoli Rong,
  • Xia Yao,
  • Haohui Fang,
  • Johns Saji,
  • Yu Qian,
  • Jia-Xuan Gu,
  • Meng-Yuan Yang,
  • Peng Wei,
  • Cai-Rui Liu,
  • Bin Chen,
  • Pian-Pian Zhao,
  • Ching-Lung Cheung,
  • Lin Bo,
  • Hou-Feng Zheng

摘要

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. 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.

Methods

We 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.

Results

CREB1 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.

Conclusions

Our 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.