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
• 负责人: Lu-Lin Jiang
• 金额: $ 12.99万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2022-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10203745
• 关键词: ALS patients; Abeta clearance; Affect; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; American; Amyloid beta-Protein; Amyotrophic Lateral Sclerosis; Anti-Inflammatory Agents; Astrocytes; Attenuated; Brain; Cells; ChIP-seq; Complex; Degenerative Disorder; Deposition; Disease; Functional disorder; Future; Genes; Genetic; Glial Fibrillary Acidic Protein; Gliosis; Glutamate Transporter; Glutamates; Homeostasis; Human; Immune response; Immunologic Receptors; Impairment; Inflammation Mediators; Injections; Injury; Knock-out; Late Onset Alzheimer Disease; Link; Longevity; Mediating; Memory impairment; Microglia; Molecular; Morphology; Motor Neurons; Mus; Mutation; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Onset of illness; Parkinson Disease; Pathogenesis; Pathogenicity; Pathologic; Pathology; Pathway interactions; Phase; Proteins; RNA Splicing; Regulation; Reporting; Role; Sampling; Senile Plaques; Signal Transduction; Single Nucleotide Polymorphism; Specific qualifier value; Spinal Cord; Stimulus; Synapses; TREM2 gene; Testing; Therapeutic Studies; Transcript; Transgenic Organisms; Up-Regulation; Virus; Work; abeta accumulation; astrogliosis; behavioral impairment; conditional knockout; excitotoxicity; extracellular; gamma secretase; genome wide association study; genomic locus; glial activation; insight; knockout animal; mouse model; mutant mouse model; nervous system disorder; neuroinflammation; neuron loss; new therapeutic target; novel; overexpression; proteostasis; proteotoxicity; restoration; superoxide dismutase 1; tau Proteins; tau aggregation; transcriptome sequencing; transcriptomics

PROJECT SUMMARY Alzheimer's disease (AD) is the most common neurodegenerative disease affecting over 3 million Americans yearly, and features the extracellular accumulation of β-amyloid, intracellular tau aggregates, and aberrant glial pathology. Glial dysfunction can trigger excitotoxicity and neuroinflammation, which is invariably linked to AD pathogenesis. Reactive astrocyte and microglia triggers in AD pathogenesis are not yet clear. Previously, I identified a novel ER component, membralin (TMEM259), as an important disease modifier in the pathogenesis of AD and Amyotrophic Lateral Sclerosis (ALS). Membralin can modulate the integrity and activity of the γ-secretase complex, and downregulating membralin expression in a mouse model of AD (TgCRND8) can exacerbate 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-specific membralin deletion can manifest severe neuroinflammatory pathological consequences, as demonstrated by robust elevation of gliotic markers including GFAP (astrocytes), IBA1 and CD68 (microglia). Transcriptomic analysis of astrocyte conditional knockout animals confirms the upregulation of genes associated with gliosis, neuroinflammation and abnormal immune response. Membralin levels are reduced in both AD brain and ALS spinal cord. Excitotoxicity, EAAT2 dysfunction and gliosis are common pathological features in AD and ALS. Moreover, a recent genome- wide association (GWAS) study demonstrated 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 molecular triggering mechanisms in 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.

项目摘要 阿尔茨海默氏病（AD）是影响超过300万美国人的最常见神经退行性疾病 每年都有β-淀粉样蛋白，细胞内tau骨料和异常神经胶质的细胞外积累 病理。神经胶质功能障碍会触发兴奋性和神经炎症，这总是与AD相关 发病。 AD发病机理中的反应性星形胶质细胞和小胶质细胞触发因素尚不清楚。 以前，我确定了一种新型的ER成分膜蛋白（TMEM259），是一个重要的疾病修饰剂 AD和肌萎缩性侧性硬化症（ALS）的发病机理。膜可以调节完整性和活动 γ-分泌酶复合物以及AD小鼠模型（TGCRND8）中的膜表达下调 加剧Aβ病理和记忆力障碍。最近，我确定了一个非单元自主 通过调节谷氨酸介导的星形胶质细胞中谷氨酸清除机制 运输蛋白，EAAT2。通过AAV病毒注射膜升高可以显着提高EAAT2水平 并延长SOD1G93A ALS小鼠的寿命。有趣的是，星形胶质细胞特异性膜缺失可以 明显的严重神经炎症病理学后果，如gliotic升高所证明 包括GFAP（星形胶质细胞），IBA1和CD68（小胶质细胞）在内的标记。星形胶质细胞的转录组分析 有条件的基因敲除动物证实了与神经胶膜，神经炎症和 异常免疫响应。 AD脑和ALS脊髓均降低了膜林的水平。兴奋性毒性， EAAT2功能障碍和神经病是AD和ALS中常见的病理特征。而且，最近的基因组 - 广泛的关联（GWAS）研究表明膜基因基因座（也称为C19orf6 人）位于单个核苷酸多态性（SNP，RS117481827）的500 bp之内 据报道，已发作的AD和膜转录本的剪接在AD中有显着改变。那，我 假设星形胶质细胞膜途径的上调可以减弱谷氨酸兴奋性和 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，我将表征与膜相关的分子机制 星形胶质细胞功能和解剖反应性星形胶质细胞中的分子触发机制（AIM 1）。我会确定 星形胶质蛋白神经炎症途径的调节是否可以改变AD的致病作用 鼠标模型（AIM 2）。在本研究的R00阶段，我将研究依赖膜蛋白的调节 小胶质细胞中的星形胶质细胞TREM2依赖性大坝开关（AIM 3）。拟议的研究表征了神经胶质病 AD中的诱导机制将提供有关神经保护膜相关的星形胶质细胞途径的见解 这可以通过细胞自主和非细胞来限制谷氨酸能兴奋性和神经炎症 自主机制。在完成这项研究的目标时，我们可以定义新的治疗靶向 通过调节AD中的神经胶质功能的策略。