Dissect regulation of glial nets surrounding amyloid plaques in Alzheimer's disease

剖析阿尔茨海默病中淀粉样斑块周围神经胶质网的调节

基本信息

项目摘要

PROJECT SUMMARY The pathophysiology of Alzheimer’s disease (AD) remains unclear. Amyloid plaques are surrounded by reactive astrocytes and microglia, forming glial nets that affect amyloid spreading and inflammatory milieu. However, the mechanisms of inter-glial communication in glial nets are poorly understood. Our recent integrated network analysis of -omics data from late-onset AD patients identified the axon guidance receptor Plexin-B1 as a hub gene in an astrocyte-specific subnetwork. We have confirmed that Plexin-B1 is predominantly expressed in astrocytes and that it is upregulated in glial nets of AD patients. Remarkably, our pilot study with an amyloidogenic mouse model of AD showed that Plexin-B1 deletion markedly altered the structure of peri-plaque glial nets. Plexin-B1 deletion resulted in attenuated astrocyte reactivity, reduced cellular spacing of glial nets, and a higher coverage of plaques by microglia, leading to a shift of plaques to a dense core type. These changes of glial nets were associated with an overall reduction in plaque burden and neuritic dystrophy. Here we will expand our preliminary studies to further test the central hypothesis that glial activation and cellular interactions in glial nets, as regulated by Plexin-B1, affect amyloid aggregates and neurotoxicity in AD. Blocking Plexin-B1 may thus present a new opportunity to attenuate astrocyte reactivity in glial nets, reducing amyloid burden and neuroinflammation, thereby slowing down AD progression. In Aim 1, we aim to build cell type-specific glial signaling networks in AD, and to identify Plexin-B1-mediated gene modules in glial nets. We will analyze single cell transcriptomic data from both AD patients and AD mice (with and without Plexin-B1 deletion) to define coregulated gene networks in reactive astrocytes and activated microglia that are associated with Plexin-B1 signaling. In Aim 2, we will carry out a series of functional assays in glial cultures to study the role of Plexin-B1 in mediating astrocyte activation upon amyloid challenge. Human iPSC-derived astrocytes with Plexin-B1 deletion by CRISPR-Cas will be compared to primary astrocytes from Plexin-B1 mutant mice. We will then model in astrocyte/microglia co-cultures glial interactions in response to amyloid challenge in dependence of Plexin- B1. In Aim 3, we will conduct in vivo studies using mouse AD models to investigate in detail the impact of Plexin- B1 deletion on glial nets, plaque deposition, neuronal function and cognitive performance. Both an amyloidogenic and a tauopathy model of AD will be evaluated at early and advanced stages. We expect to demonstrate that Plexin-B1 deletion leads to attenuated astrocyte reactivity in glial nets, reduced cellular spacing, increased microglial coverage of amyloid plaques, and a shift to dense-core plaques and thus less neurotoxicity, as indicated by pilot data. Altogether, our study will provide new insights into the contribution of glial nets and Plexin- B1 to the neurodegenerative processes in AD, thus providing new therapeutic angles.
项目摘要 阿尔茨海默氏病(AD)的病理生理尚不清楚。淀粉样斑块被反应性围绕 星形胶质细胞和小胶质细胞,形成影响淀粉样蛋白扩散和炎症环境的神经胶质网。但是, 胶质网中缘层间通信的机制知之甚少。我们最近的集成网络 分析来自晚期AD患者的-omics数据将轴突引导接收器丛蛋白B1识别为中心 星形胶质细胞特异性子网中的基因。我们已经确认plexin-b1主要表达 星形胶质细胞并在AD患者的神经胶网中进行了更新。值得注意的是,我们的试点研究 AD的淀粉样小鼠模型表明,Plexin-B1缺失明显改变了斑纹的结构 神经胶网。 Plexin-B1缺失导致星形胶质细胞反应性减弱,胶质网的细胞间距降低, 小胶质细胞对斑块的覆盖范围更高,导致斑块转移到密集的核心类型。这些变化 神经胶质网与牙菌斑和神经性营养不良的总体减少有关。我们会在这里 扩展我们的初步研究,以进一步检验胶质激活和细胞相互作用的中心假设 在神经胶质网中,受plexin-b1的调节,会影响AD中的淀粉样蛋白聚集体和神经毒性。阻塞plexin-b1 因此,可能会带来新的机会来减轻神经胶质网中星形胶质细胞的反应性,减少淀粉样蛋白伯恩和 神经炎症,从而减慢了广告的进展。在AIM 1中,我们旨在建立特定细胞类型的神经胶质 AD中的信号网络,并鉴定胶质网中的Plexin-B1介导的基因模块。我们将分析单个 来自AD患者和AD小鼠的细胞转录数据(带有和没有Plexin-B1缺失)以定义 反应性星形胶质细胞和激活的小胶质细胞中的基因网络与Plexin-B1相关 信号。在AIM 2中,我们将在神经胶质培养物中进行一系列功能评估,以研究Plexin-B1的作用 在淀粉样蛋白挑战时介导星形胶质细胞激活时。带有plexin-b1的人IPSC衍生的星形胶质细胞 将CRISPR-CAS的缺失与Plexin-B1突变小鼠的原代星形胶质细胞进行比较。然后我们将建模 在星形胶质细胞/小胶质细胞共培养中,对淀粉样蛋白挑战的胶质相互作用依赖于淀粉样蛋白 - B1。在AIM 3中,我们将使用小鼠AD模型进行体内研究,以详细研究丛蛋白的影响 B1缺失在神经胶质网,牙菌斑沉积,神经元功能和认知性能上。两者都是淀粉样蛋白生成的 并且将在早期和高级阶段评估AD的Tauopathy模型。我们希望证明 PLEXIN-B1缺失导致神经胶质网中的星形胶质细胞反应性减弱,细胞间距降低,增加 淀粉样斑块的小胶质细胞覆盖范围,转向致密斑块,因此较少的神经毒性,如 通过飞行员数据指示。总之,我们的研究将为神经胶质网和丛蛋白的贡献提供新的见解。 B1到AD中的神经退行性过程,从而提供了新的治疗角度。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Roland Horst Friedel其他文献

Roland Horst Friedel的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Roland Horst Friedel', 18)}}的其他基金

Tracing Hypoxic State and Hypoxia Memory in Glioblastoma Progression
追踪胶质母细胞瘤进展中的缺氧状态和缺氧记忆
  • 批准号:
    10541195
  • 财政年份:
    2021
  • 资助金额:
    $ 180万
  • 项目类别:
Tracing hypoxic state and hypoxia memory in glioblastoma progression
追踪胶质母细胞瘤进展中的缺氧状态和缺氧记忆
  • 批准号:
    10387061
  • 财政年份:
    2021
  • 资助金额:
    $ 180万
  • 项目类别:
Plexin-B2 Function in Glioma Invasion
Plexin-B2 在神经胶质瘤侵袭中的功能
  • 批准号:
    10296785
  • 财政年份:
    2016
  • 资助金额:
    $ 180万
  • 项目类别:
Plexin-B2 function in glioma invasion and glioma stem cell maintenance
Plexin-B2 在神经胶质瘤侵袭和神经胶质瘤干细胞维持中的功能
  • 批准号:
    9900877
  • 财政年份:
    2016
  • 资助金额:
    $ 180万
  • 项目类别:
Plexin-B2 function in glioma invasion and glioma stem cell maintenance
Plexin-B2 在神经胶质瘤侵袭和神经胶质瘤干细胞维持中的功能
  • 批准号:
    9106872
  • 财政年份:
    2016
  • 资助金额:
    $ 180万
  • 项目类别:
Plexin-B2 Function in Glioma Invasion
Plexin-B2 在神经胶质瘤侵袭中的功能
  • 批准号:
    10655424
  • 财政年份:
    2016
  • 资助金额:
    $ 180万
  • 项目类别:
Tracking the in vivo proliferative history of human glioma-derived stem cells
追踪人胶质瘤干细胞的体内增殖史
  • 批准号:
    8622863
  • 财政年份:
    2013
  • 资助金额:
    $ 180万
  • 项目类别:
Tracking the in vivo proliferative history of human glioma-derived stem cells
追踪人胶质瘤干细胞的体内增殖史
  • 批准号:
    8742022
  • 财政年份:
    2013
  • 资助金额:
    $ 180万
  • 项目类别:

相似海外基金

Investigating the role of CSF production and circulation in aging and Alzheimer's disease
研究脑脊液产生和循环在衰老和阿尔茨海默病中的作用
  • 批准号:
    10717111
  • 财政年份:
    2023
  • 资助金额:
    $ 180万
  • 项目类别:
CLEC7A in microglia biology and Alzheimer's disease
CLEC7A 在小胶质细胞生物学和阿尔茨海默病中的作用
  • 批准号:
    10659940
  • 财政年份:
    2023
  • 资助金额:
    $ 180万
  • 项目类别:
Role of oligodendrocyte-derived IL-33 in brain aging and Alzheimer's disease
少突胶质细胞来源的 IL-33 在大脑衰老和阿尔茨海默病中的作用
  • 批准号:
    10736636
  • 财政年份:
    2023
  • 资助金额:
    $ 180万
  • 项目类别:
A 5-HTergic DRN vCA1 circuit and Alzheimer's disease
5-HTergic DRN vCA1 回路与阿尔茨海默病
  • 批准号:
    10740050
  • 财政年份:
    2023
  • 资助金额:
    $ 180万
  • 项目类别:
Role of apoE-mediated meningeal lymphatic remodeling in the pathophysiology of Alzheimer’s disease
apoE 介导的脑膜淋巴重塑在阿尔茨海默病病理生理学中的作用
  • 批准号:
    10734287
  • 财政年份:
    2023
  • 资助金额:
    $ 180万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了