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

ABSTRACT:

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

SUBMITTER: Rong X 

PROVIDER: S-EPMC12560359 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature