A Role of Astrocyte and Microglia Interplay in Alzheimer's Disease

星形胶质细胞和小胶质细胞相互作用在阿尔茨海默病中的作用

基本信息

项目摘要

Project Summary/Abstract Alzheimer’s disease (AD) is the most common neurodegenerative disease affecting over 3 million Americans yearly, with extracellular accumulation of β-amyloid and intracellular tau aggregates, and aberrant glial activation pathologies. Glial dysfunction can trigger excitotoxicity and neuroinflammation, which is invariably involved in AD pathogenesis. However, how astrocyte and microglia become reactive in the pathogenesis of AD is not clear. Previously, I have identified a novel ER component, membralin (TMEM259), as an important disease modifier in the pathogenesis of AD and Amytrophic Lateral Sclerosis (ALS). First, I find that membralin can modulate the integrity and activity of the γ-secretase complex. I found that knocking down of membralin expression in a mouse model of AD (TgCRND8) can exacerbated Aβ pathology and memory impairment. More recently, I have identified a non-cell-autonomous glutamate clearance mechanism in astrocytes mediated by membralin through regulation of the glutamate transporter, EAAT2. Elevation of membralin through AAV virus injection can significantly increase EAAT2 levels and extend the lifespan of the SOD1G93A ALS mice. Interestingly, astrocyte-deletion of membralin can lead a severe neuroinflammatory pathologies, as shown by remarkable elevation of gliosis markers: GFAP (astrocytes), IBA1 and CD68 (microglia). Transcriptomic analysis of astrocyte conditional knockout animals confirms the upregulation of genes associated to gliosis, neuroinflammation and abnormal immune response. I found reduced membralin levels in brain samples from both AD and ALS patients. Excitotoxicity, EAAT2 dysfunction and gliosis are common pathological features in AD and ALS. Moreover, a recent genome-wide association (GWAS) study has shown that the membralin gene locus (also known as C19ORF6 in human) is located within 500 bp of a single nucleotide polymorphism (SNP, rs117481827) tightly associated with late-onset AD, and splicing of membralin transcripts has been reported to be significantly altered in AD. Thus, I hypothesize that upregulation of astrocytic membralin pathways can attenuate glutamate excitotoxicity and modulate microglial-dependent pathogenic effects in AD. In the K99 phase of this study, I will characterize molecular mechanisms underlying membralin-associated astrocyte function and dissect the induction mechanisms of reactive astrocytes (Aim 1). I will determine whether modulation of astrocytic membralin neuroinflammatory pathways can alter pathogenic effects in an AD mouse model (Aim 2). In the R00 phase of this study, I will investigate modulation of a membralin-dependent astrocytic TREM2-dependent DAM switch in microglia (Aim 3). The proposed study characterizing the gliosis induction mechanisms in AD, will provide insight into neuroprotective membralin-associated astrocyte pathways that can limit glutamatergic excitotoxicity and neuroinflammation through cell-autonomous and non-cell autonomous mechanisms. In completing the aims of this study, we may define new therapeutic targeting strategies through modulation of glial function in AD.
项目总结/摘要 阿尔茨海默病(AD)是最常见的神经退行性疾病,影响超过300万美国人 随着β-淀粉样蛋白和细胞内tau聚集物的细胞外积累以及异常的神经胶质活化, 病理学。神经胶质功能障碍可引发兴奋性毒性和神经炎症,这总是涉及神经胶质细胞损伤。 AD发病机制然而,星形胶质细胞和小胶质细胞如何在AD的发病机制中变得反应性尚不清楚。 以前,我已经确定了一种新的ER组分,membralin(TMEM 259),作为一种重要的疾病调节剂, AD和肌萎缩侧索硬化症(ALS)的发病机制。首先,我发现membralin可以调节 γ-分泌酶复合物的完整性和活性。我发现在小鼠中敲低membralin的表达 AD模型(TgCRND 8)可加重Aβ病理改变和记忆障碍。最近,我发现 Membralin介导的星形胶质细胞谷氨酸非自主清除机制 谷氨酸转运体EAAT 2的基因通过AAV病毒注射提高膜蛋白可以显著地 增加EAAT 2水平并延长SOD 1G 93 A ALS小鼠的寿命。有趣的是, Membralin可导致严重的神经炎性病理,如胶质增生显著升高所示 标志物:GFAP(星形胶质细胞)、IBA 1和CD 68(小胶质细胞)。星形胶质细胞条件分化的转录组学分析 敲除动物证实了与神经胶质增生、神经炎症和异常 免疫反应我发现AD和ALS患者的大脑样本中membralin水平降低。 兴奋毒性、EAAT 2功能障碍和胶质增生是AD和ALS的共同病理特征。而且 最近的全基因组关联(GWAS)研究表明,membralin基因位点(也称为 人类C19 ORF 6)位于500 bp内的一个单核苷酸多态性(SNP,rs 117481827), 与晚发性AD相关,据报道,膜蛋白转录本的剪接发生了显著改变, 在AD中。因此,我假设星形胶质细胞膜蛋白通路的上调可以减弱谷氨酸, 兴奋性毒性和调节AD中的小胶质细胞依赖性致病作用。 在本研究的K99阶段,我将描述膜蛋白相关的分子机制。 星形胶质细胞的功能和解剖反应性星形胶质细胞的诱导机制(目的1)。我将决定 调节星形胶质细胞膜神经炎症通路可改变AD小鼠的致病作用 模型(目标2)。在本研究的R 00阶段,我将研究膜蛋白依赖性星形胶质细胞的调节, 小胶质细胞中的TREM 2依赖性DAM开关(Aim 3)。拟进行的表征神经胶质增生诱导的研究 机制,将提供深入了解神经保护膜蛋白相关的星形胶质细胞途径, 通过细胞自主性和非细胞自主性限制神经元兴奋性毒性和神经炎症 机制等在完成本研究的目的时,我们可以通过以下方式定义新的治疗靶向策略: AD中神经胶质功能的调节。

项目成果

期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
mRNA translation in astrocytes controls hippocampal long-term synaptic plasticity and memory.
星形胶质细胞中的 mRNA 翻译控制着海马的长期突触可塑性和记忆。
  • DOI:
    10.1073/pnas.2308671120
  • 发表时间:
    2023
  • 期刊:
  • 影响因子:
    11.1
  • 作者:
    Sharma,Vijendra;Oliveira,MauricioM;Sood,Rapita;Khlaifia,Abdessattar;Lou,Danning;Hooshmandi,Mehdi;Hung,Tzu-Yu;Mahmood,Niaz;Reeves,Maya;Ho-Tieng,David;Cohen,Noah;Cheng,Po-Chieh;Rahim,MirMunirA;Prager-Khoutorsky,Masha;Kaufman,
  • 通讯作者:
    Kaufman,
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Lu-Lin Jiang其他文献

Lu-Lin Jiang的其他文献

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{{ truncateString('Lu-Lin Jiang', 18)}}的其他基金

A Role of Astrocyte and Microglia Interplay in Alzheimer's Disease
星形胶质细胞和小胶质细胞相互作用在阿尔茨海默病中的作用
  • 批准号:
    10203745
  • 财政年份:
    2020
  • 资助金额:
    $ 13.13万
  • 项目类别:
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