Transcriptional regulation of neuroprotective microglia subtypes in health and disease

健康和疾病中神经保护性小胶质细胞亚型的转录调控

基本信息

项目摘要

Project Summary This proposal addresses a novel way in which microglia functional states are regulated by the transcription factor PU.1 in the context of amyloid pathology and its potential contribution to neuroprotection against Alzheimer’s disease (AD). The expression level of PU.1 is crucial for instructing commitment to myeloid versus lymphoid lineages and is enriched in microglia. PU.1 also determines the inflammatory activation state of macrophages by priming cis-regulatory regions to elicit appropriate gene expression upon stimulation. Recently, genome wide association studies (GWAS) have identified a variant in Spi1 (encoding PU.1) that modulates AD risk. Unlike other variants, the Spi1 variant is unique in that it leads to a reduction in PU.1 expression and has a protective effect against AD risk. In a 5xFAD amyloid mouse model of AD, I observed heterogeneous protein expression of PU.1 in microglia. Recent work supports the idea that specific microglia activation states have unique impacts on AD pathogenesis. The Disease Associated Microglia (DAMs) are thought to serve a protective role in AD by robustly responding to amyloid plaques whereas inflammatory populations potentially play a harmful role in disease. I hypothesize that low PU.1 expression in microglia induces neuroprotective functional states in microglia against AD. We generated genetic mouse models that increase (Spi1cOE) or decrease (Spi1cKD) PU.1 expression specifically in microglia and crossed them to the 5xFAD amyloid disease model. Ribosomal profiling of these microglia revealed significant bulk transcriptional changes. To understand how PU.1 expression level regulates microglia activation states during amyloid pathology, I performed single nuclei RNA-sequencing. These new data reveal that Spi1cKD in 5xFAD favors microglia states associated with neuroprotection (DAM) while attenuating the proportion of cells in toxic states (inflammatory). Knowing the location of these microglia in relation to amyloid plaques will enhance our understanding of where engagement of such states occur and where these microglia may be exerting protective or harmful effects. In my first aim, I will use multiplexed error-robust in situ hybridization (MERFISH) to spatially identify microglia in DAM and inflammatory activation states with Spi1cKD or Spi1cOE in 5xFAD. In addition to these transcriptional changes, we showed a reduction in the complement protein C1qa in Spi1cKD 5xFAD animals. We further found that Spi1cKD microglia prevented synapse loss that is characteristic in human AD and recapitulated in the 5xFAD model. It has been shown that pathological activation of complement occurs with inflammatory activation and contributes to synapse loss in AD. Therefore, I propose to assess the production of C1qa by microglia with differential PU.1 expression level in vitro and synaptic co-localization of C1qa in 5xFAD mice with Spi1cKD and Spi1cOE microglia.
项目摘要 这一建议提出了一种新的方式,其中小胶质细胞的功能状态是由转录因子调节 淀粉样蛋白病理学背景下的PU.1及其对阿尔茨海默病神经保护的潜在贡献 疾病(AD)。PU.1的表达水平对于指导向髓系和淋巴系的定向是至关重要的。 谱系,并富含小胶质细胞。PU.1还决定巨噬细胞的炎症活化状态 通过引发顺式调节区以在刺激时引发适当的基因表达。最近,全基因组 关联研究(GWAS)已经确定了Spi1(编码PU.1)中调节AD风险的变体。不像 Spi1变体是独特的,因为它导致PU.1表达的减少,并具有保护性, 对AD风险的影响。在5xFAD淀粉样蛋白小鼠AD模型中,我观察到异质性蛋白表达, 在小胶质细胞中的PU.1。最近的工作支持这样的观点,即特定的小胶质细胞激活状态具有独特的影响 AD发病机制疾病相关小胶质细胞(DAM)被认为通过以下方式在AD中起保护作用: 对淀粉样蛋白斑块有强烈的反应,而炎性细胞群在 疾病我假设小胶质细胞中PU.1的低表达诱导了神经保护功能状态, 小胶质细胞抗AD我们建立了增加(Spi1cOE)或减少(Spi1cKD)的遗传小鼠模型。 PU.1在小胶质细胞中特异性表达,并将它们与5xFAD淀粉样蛋白疾病模型交叉。核糖体 这些小胶质细胞的谱显示了显著的大量转录变化。了解PU.1表达 水平调节淀粉样蛋白病理过程中的小胶质细胞激活状态,我进行了单核RNA测序。 这些新数据表明,5xFAD中的Spi1cKD有利于与神经保护(DAM)相关的小胶质细胞状态 同时减少处于毒性状态(炎症)的细胞的比例。知道这些小胶质细胞在 与淀粉样蛋白斑块的关系将增强我们对这种状态发生的位置和位置的理解。 这些小胶质细胞可能发挥保护或有害作用。在我的第一个目标中,我将使用多路复用的错误鲁棒 原位杂交(MERFISH)在空间上识别DAM中的小胶质细胞和炎症激活状态, 5xFAD中的Spi1cKD或Spi1cOE。除了这些转录上的变化,我们还显示了在转录水平上的减少。 Spi1cKD 5xFAD动物的补体蛋白C1qa。我们进一步发现Spi1cKD小胶质细胞阻止了 突触丢失是人类AD的特征,并在5xFAD模型中重现。已经显示 补体的病理性活化与炎性活化一起发生,并导致AD中的突触丧失。 因此,我建议在体外评估具有不同PU.1表达水平的小胶质细胞产生C1qa 以及C1qa在具有Spi1cKD和Spi1cOE小胶质细胞的5xFAD小鼠中的突触共定位。

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