细胞生物学
神经退行性变
细胞外
核运输
基因表达
生物
τ蛋白
细胞内
化学
分子生物学
细胞核
基因
阿尔茨海默病
核心
生物化学
病理
疾病
医学
作者
Xuehan Sun,Guillermo Eastman,Shuang Yu,Subhi Saibaba,Ana K. Oliveira,John R. Lukens,Andrés Norambuena,Joseph A. Thompson,Michael D. Purdy,Kelly A. Dryden,Evelyn Pardo,James W. Mandell,George S. Bloom
摘要
Abstract INTRODUCTION Neuronal nuclei are normally smoothly surfaced. In Alzheimer's disease (AD) and other tauopathies, though, they often develop invaginations. We investigated mechanisms and functional consequences of neuronal nuclear invagination in tauopathies. METHODS Nuclear invagination was assayed by immunofluorescence in the brain, and in cultured neurons before and after extracellular tau oligomer (xcTauO) exposure. Nucleocytoplasmic transport was assayed in cultured neurons. Gene expression was investigated using nanoString nCounter technology and quantitative reverse transcription polymerase chain reaction. RESULTS Invaginated nuclei were twice as abundant in human AD as in cognitively normal adults, and were increased in mouse neurodegeneration models. In cultured neurons, nuclear invagination was induced by xcTauOs by an intracellular tau‐dependent mechanism. xcTauOs impaired nucleocytoplasmic transport, increased histone H3 trimethylation at lysine 9, and altered gene expression, especially by increasing tau mRNA. DISCUSSION xcTauOs may be a primary cause of nuclear invagination in vivo, and by extension, impair nucleocytoplasmic transport and induce pathogenic gene expression changes. Highlights Extracellular tau oligomers (xcTauOs) cause neuronal nuclei to invaginate. xcTauOs alter nucleocytoplasmic transport, chromatin structure, and gene expression. The most upregulated gene is MAPT , which encodes tau. xcTauOs may thus drive a positive feedback loop for production of toxic tau.
科研通智能强力驱动
Strongly Powered by AbleSci AI