Alzheimer's Disease-Associated circPDE4B Interacts with GEMIN5 to Regulate Translation

In the intricate landscape of Alzheimer's disease (AD) pathology, circular RNAs (circRNA) are emerging as influential players, orchestrating crucial aspects of gene expression, synaptic plasticity, and neuronal function. In this study, we characterize the biological role of circPDE4B, a highly abundant circRNA that is markedly downregulated in AD across brain regions. Unlike most circRNAs, circPDE4B is expressed at substantially higher levels than its linear PDE4B transcript, suggesting a distinctive regulatory significance. Functional analyses in neuronal progenitor cells revealed that circPDE4B reduction triggers a translational stress response, indicating its critical role in maintaining protein synthesis homeostasis. Pulldown of circPDE4B identified the translation regulatory factor GEMIN5 as a highly specific, major interactor, and GEMIN5 knockdown showed it as a key mediator of actions of circPDE4B on translation. Loss of circPDE4B also reduced mTOR levels and subsequently enhanced autophagic flux. Notably, circPDE4B downregulation was sufficient to mitigate tau pathology in a 3D human assembloid model of tauopathy. We also identified a subset of AD-associated miRNAs interacting with circPDE4B, implicating additional layers of post-transcriptional regulation. Collectively, these findings define circPDE4B as a multifunctional regulator of neuronal homeostasis that integrates translational control, autophagy, and miRNA-mediated pathways, illuminating its potential role in the stress response and pathophysiology of AD. Overall design: To identify potential miRNA partners of circPDE4B, we performed RNA immunoprecipitation (RIP) targeting circPDE4B in neuronal progenitor cells (NPCs). Small RNAs were isolated from the immunoprecipitates and subjected to small RNA sequencing (smRNA-seq). The experiment included five biological replicates for the circPDE4B IP and five for the scrambled control IP.