Conserved Neuronal circRNA Alterations and Their Mechanistic Roles in Alzheimer’s Disease

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder in which changes in gene regulation contribute to neuronal dysfunction and cognitive decline. While considerable attention has focused on protein-coding genes, far less is known about the role of circular RNAs (circRNAs), a class of highly stable, brain-enriched non-coding RNAs that can influence gene regulation. Although circRNA abnormalities have been identified in postmortem AD brains, it remains unclear whether these changes contribute to disease progression or simply reflect later-stage pathology. Understanding when circRNA dysregulation occurs and how it contributes to AD could reveal new molecular pathways and therapeutic opportunities for early intervention.

Dr. Wang proposes to address this question by identifying conserved neuronal circRNA alterations associated with AD progression and determining their functional significance. The team has developed experimental and computational approaches for sensitive detection and characterization of circRNAs and has generated preliminary evidence supporting widespread circRNA dysregulation across AD-related experimental systems. Their findings suggest that selected circRNAs may influence neuronal function and AD-related molecular processes, providing a strong rationale for further mechanistic investigation. They hypothesize that disruption of circRNA-mediated gene regulation contributes to neuronal dysfunction during AD progression.

The study will pursue two complementary goals. First, the team will define conserved neuronal circRNA changes across different stages and experimental models of AD, with an emphasis on identifying alterations that are relevant to human disease. Second, they will investigate the molecular mechanisms through which prioritized circRNAs contribute to neuronal dysfunction and determine whether modulation of these pathways has the potential to ameliorate AD-related cellular and pathological changes.

If successful, this work will help establish whether circRNA dysregulation is an early contributor to AD rather than simply a consequence of neurodegeneration. By defining previously underexplored RNA regulatory mechanisms involved in neuronal dysfunction, the study could reveal a new class of therapeutic targets and biomarkers for early detection and intervention in AD.