한빛사논문
- 조회459
Byungwook Kim 1,2, Luke Child Dabin 1,2,9, Mason Douglas Tate 2,3,9, Hande Karahan 1,2,9, Ahmad Daniel Sharify 1,2, Dominic J. Acri 1,2,3, Md Mamun Al-Amin 1,2, Stéphanie Philtjens 1,2, Daniel Curtis Smith 1,2,3, H. R. Sagara Wijeratne 1,2,4, Jung Hyun Park 1,2,5,6, Mathias Jucker 7,8 & Jungsu Kim 1,2,3,*
1Department of Medical & Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
2Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
3Medical Neuroscience Graduate Program, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
4Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
5Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN 47405, USA.
6Program in Neuroscience, Indiana University, Bloomington, IN 47405, USA.
7German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
8Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
9These authors contributed equally: Luke Child Dabin, Mason Douglas Tate, Hande Karahan
*Corresponding author: correspondence to Jungsu Kim
Abstract
SPI1 was recently reported as a genetic risk factor for Alzheimer’s disease (AD) in large-scale genome-wide association studies. However, it is unknown whether SPI1 should be downregulated or increased to have therapeutic benefits. To investigate the effect of modulating SPI1 levels on AD pathogenesis, we performed extensive biochemical, histological, and transcriptomic analyses using both Spi1-knockdown and Spi1-overexpression mouse models. Here, we show that the knockdown of Spi1 expression significantly exacerbates insoluble amyloid-β (Aβ) levels, amyloid plaque deposition, and gliosis. Conversely, overexpression of Spi1 significantly ameliorates these phenotypes and dystrophic neurites. Further mechanistic studies using targeted and single-cell transcriptomics approaches demonstrate that altered Spi1 expression modulates several pathways, such as immune response pathways and complement system. Our data suggest that transcriptional reprogramming by targeting transcription factors, like Spi1, might hold promise as a therapeutic strategy. This approach could potentially expand the current landscape of druggable targets for AD.
논문정보
- Research article
- 2024년 05월 (BRIC 등록일 2024-05-13)
- 국외 연구진
- 생명과학 > 신경생물학
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