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.

最近，在大规模全基因组关联研究中，SPI1被报道为阿尔茨海默病 (AD) 的遗传风险因素。然而，尚不清楚SPI1是否应该下调或增加才能产生治疗效果。为了研究调节SPI1水平对 AD 发病机制的影响，我们使用Spi1敲低和Spi1过表达小鼠模型进行了广泛的生化、组织学和转录组学分析。在这里，我们发现Spi1表达的敲低会显着加剧不溶性淀粉样蛋白-β (Aβ) 水平、淀粉样蛋白斑沉积和神经胶质增生。相反，Spi1的过度表达可显着改善这些表型和营养不良的神经突。使用靶向和单细胞转录组学方法进行的进一步机制研究表明，改变Spi1表达可调节多种途径，例如免疫反应途径和补体系统。我们的数据表明，通过靶向转录因子（如Spi1 ）进行转录重编程可能有望成为一种治疗策略。这种方法可能会扩大目前 AD 药物靶点的范围。