Identification of pathological pathways centered on circRNA dysregulation in association with irreversible progression of Alzheimer’s disease

作者：Feng Wang, Yangping Li, Huifeng Shen, Paula Martínez-Feduchi, Xingyu Ji, Peng Teng, Siddharth Krishnakumar, Jian Hu, Li Chen, Yue Feng, Bing Yao · 发表于：Genome Medicine · 年份：2024 · DOI：10.1186/s13073-024-01404-6 · 被引用次数：12 · 研究领域：Circular RNAs in diseases、MicroRNA in disease regulation、RNA Research and Splicing

BACKGROUND: Circular RNAs (circRNAs) are highly stable regulators, often accumulated in mammalian brains and thought to serve as "memory molecules" that govern the long process of aging. Mounting evidence demonstrated circRNA dysregulation in the brains of Alzheimer's disease (AD) patients. However, whether and how circRNA dysregulation underlies AD progression remains unexplored. METHODS: We combined Poly(A)-tailing/RNase R digestion experimental approach with CARP, our published computational framework using pseudo-reference alignment for more sensitive and accurate circRNA detection to identify genome-wide circRNA dysregulation and their downstream pathways in the 5xFAD mouse cerebral cortex between 5 and 7 months of age, a critical window marks the transition from reversible to irreversible pathogenic progression. Dysregulated circRNAs and pathways associated with disease progression in 5xFAD cortex were systematically compared with circRNAs affected in postmortem subcortical areas of a large human AD cohort. A top-ranked circRNA conserved and commonly affected in AD patients and 5xFAD mice was depleted in cultured cells to examine AD-relevant molecular and cellular changes. RESULTS: We discovered genome-wide circRNA alterations specifically in 5xFAD cortex associated with AD progression, many of which are commonly dysregulated in the subcortical areas of AD patients. Among these circRNAs, circGigyf2 is highly conserved and showed the highest net reduction specifically in...