神经炎症
神经退行性变
小胶质细胞
生物
转录组
MECP2
转录因子
细胞生物学
基因
遗传学
基因表达
表型
免疫学
疾病
医学
炎症
病理
作者
William T. Ralvenius,Alison E. Mungenast,Hannah Woolf,Marilyn M. Huston,Tyler Z. Gillingham,Stephen K. Godin,Jay Penney,Hugh P. Cam,Fan Gao,Celia G. Fernandez,Barbara Czakó,Yaíma L. Lightfoot,William J. Ray,Adrian Beckmann,Alison M. Goate,Edoardo Marcora,Carmen Romero‐Molina,Pinar Ayata,Anne Schaefer,Elizabeta Gjoneska,Li‐Huei Tsai
摘要
Pervasive neuroinflammation occurs in many neurodegenerative diseases, including Alzheimer’s disease (AD). SPI1/PU.1 is a transcription factor located at a genome-wide significant AD-risk locus and its reduced expression is associated with delayed onset of AD. We analyzed single-cell transcriptomic datasets from microglia of human AD patients and found an enrichment of PU.1-binding motifs in the differentially expressed genes. In hippocampal tissues from transgenic mice with neurodegeneration, we found vastly increased genomic PU.1 binding. We then screened for PU.1 inhibitors using a PU.1 reporter cell line and discovered A11, a molecule with anti-inflammatory efficacy and nanomolar potency. A11 regulated genes putatively by recruiting a repressive complex containing MECP2, HDAC1, SIN3A, and DNMT3A to PU.1 motifs, thus representing a novel mechanism and class of molecules. In mouse models of AD, A11 ameliorated neuroinflammation, loss of neuronal integrity, AD pathology, and improved cognitive performance. This study uncovers a novel class of anti-inflammatory molecules with therapeutic potential for neurodegenerative disorders.
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