Regulation of tau protein by circCwc27: shared pathogenic mechanisms in type 2 diabetes mellitus and Alzheimer's disease.

Background: Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) are distinct yet interconnected disorders that frequently co-occur. While insulin resistance and impaired glucose metabolism have been implicated in their shared pathogenesis, the molecular mechanisms underlying this comorbidity remain incompletely understood. Emerging evidence suggests that circular RNAs (circRNAs), particularly those enriched in neural and metabolic tissues, may play regulatory roles in both diseases.

Methods: We conducted integrated transcriptomic analyses using Gene Expression Omnibus (GEO) datasets to identify differentially expressed genes in AD and T2DM. Protein-protein interaction (PPI) network construction and enrichment analyses identified common hub genes and dysregulated pathways. Functional studies were performed in SH-SY5Y and HEK293 cell models to explore the biological impact of Circular RNA Cwc27 (circCwc27), a circRNA derived from the Cwc27 gene.

Results: Among 86 commonly upregulated genes, Cwc27 emerged as a central hub with significant connectivity in the AD-T2DM interaction network. Functional enrichment analysis revealed circCwc27's association with RNA splicing, mRNA surveillance, and PI3K-Akt signaling. Overexpression of circCwc27 increased total and phosphorylated Tau protein levels, enhanced Tau seeding activity, and reduced intracellular glycogen storage-hallmarks of AD neuropathology and metabolic dysregulation in T2DM. Notably, these effects occurred independently of Akt-GSK3β activation or APP expression, suggesting a unique regulatory axis involving Tau protein.

Conclusion: Our findings identify circCwc27 as a novel molecular bridge linking AD and T2DM via Tau upregulation and metabolic impairment. This dual role highlights its potential as both a biomarker and therapeutic target for addressing the shared pathophysiological mechanisms of neurodegeneration and metabolic disease.