神经发生
神经退行性变
生物
下调和上调
神经科学
祖细胞
表型
阿尔茨海默病
细胞生物学
疾病
干细胞
遗传学
医学
基因
病理
作者
Chiara Scopa,Samantha M. Barnada,M.E. Cicardi,Mo Singer,Davide Trotti,Marco Trizzino
标识
DOI:10.1038/s41467-023-43728-8
摘要
Abstract Adult neurogenic decline, inflammation, and neurodegeneration are phenotypic hallmarks of Alzheimer’s disease (AD). Mobilization of transposable elements (TEs) in heterochromatic regions was recently reported in AD, but the underlying mechanisms are still underappreciated. Combining functional genomics with the differentiation of familial and sporadic AD patient derived-iPSCs into hippocampal progenitors, CA3 neurons, and cerebral organoids, we found that the upregulation of the AP-1 subunit, c-Jun, triggers decondensation of genomic regions containing TEs. This leads to the cytoplasmic accumulation of HERVK-derived RNA-DNA hybrids, the activation of the cGAS-STING cascade, and increased levels of cleaved caspase-3, suggesting the initiation of programmed cell death in AD progenitors and neurons. Notably, inhibiting c-Jun effectively blocks all these downstream molecular processes and rescues neuronal death and the impaired neurogenesis phenotype in AD progenitors. Our findings open new avenues for identifying therapeutic strategies and biomarkers to counteract disease progression and diagnose AD in the early, pre-symptomatic stages.
科研通智能强力驱动
Strongly Powered by AbleSci AI