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Investigating CD33 function on microglia during Alzheimer’s disease using CRISPR nanoparticles

使用 CRISPR 纳米粒子研究阿尔茨海默病期间小胶质细胞上的 CD33 功能

基本信息

批准号：
10211028
负责人：
Sarah Christine Hopp
金额：
$ 42.56万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10211028
关键词：
AD transgenic mice Address Age Aging Alzheimer disease prevention Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease risk Amyloid Amyloid beta-Protein Animal Model Apolipoprotein E Autopsy Binding Brain CRISPR-nanoparticles Cell model Cells Characteristics Chronic Clinical Clustered Regularly Interspaced Short Palindromic Repeats Data Data Set Deposition Detection Development Disease Disease Progression Down-Regulation Environment Family Future Gene Expression Genes Genetic Polymorphism Gold Guide RNA Heterogeneity Hippocampus (Brain)Human Immune Immunosuppression Inflammatory Intervention Knock-out Lead Mediating Memory impairment Methods Microglia Mus Mutation Nerve Degeneration Neurodegenerative Disorders Pathogenesis Pathology Peripheral Phagocytes Phagocytosis Phenotype Promoter Regions Regulation Research Resistance Risk Factors Role Senile Plaques Sialic Acids Signal Pathway Specificity System TREM2 gene Testing Time Toxic effect Transgenic Animals Up-Regulation Viral amyloid formation brain cell cell type dentate gyrus differential expression experimental study familial Alzheimer disease genetic signature genome wide association study human data improved in vivo innovation knock-down member mouse model nanoparticle delivery neuroinflammation neuroprotection neurotoxicity new therapeutic target prevent protein aggregation receptor research and development response risk variant sialic acid binding Ig-like lectin single cell analysis single-cell RNA sequencing targeted nucleases targeted treatment therapeutic target transcriptomics uptake

项目摘要

Abstract Microglia, the immune cells of the brain, are key cellular players in the pathogenesis and progression of Alzheimer’s disease (AD). As the immune cells of the brain, microglia are the cell type predominantly involved in phagocytosis of protein aggregates such as amyloid b (Ab), which aggregates to form the characteristic plaques present in AD. A decrement of microglia phagocytic capability, combined with a pro-inflammatory phenotype, may lead to a brain environment permissive for Ab plaque formation. Recent genome-wide association studies have identified mutations in the immune-cell specific gene CD33, expressed almost exclusively on microglia in the brain, as a risk factor for development of AD. CD33 is a member of the Siglec family of receptors, and has an immunosuppressive effect upon detection sialic acids. Reduced expression of CD33 is protective against formation of Ab plaques by stimulating phagocytosis and altering pro-inflammatory phenotype in microglia. Thus, CD33 represents an important therapeutic target for treatment and prevention of AD. However, an appropriate timepoint for anti-CD33 treatments has not been established due to technical challenges with manipulating CD33 in the brain of transgenic animal models of AD. Here, we propose to use a brain- and microglia-validated method for delivery of CRISPR to the brain to knock down expression of CD33 at various times during the course of disease progression in a transgenic animal model of AD. We predict that downregulation of CD33 early and late in disease will differentially alter microglia phagocytosis of Ab, change plaque load, abrogate neurotoxicity, and improve memory deficits. Further, we aim to understand the heterogeneity of microglia CD33 expression in human AD patients by examining existing single-cell transcriptomics datasets. We predict that microglia with reduced CD33 will display a phagocytic and neuroprotective gene signature. We predict that this gene signature will also be evident in CD33-high and CD33- low microglia from transgenic AD mice. Finally, we will test sialic acid binding as a potential mechanism by which CD33 regulates phagocytosis of Ab. Overall, these studies will enhance our current understanding of how CD33 modifies microglia function in vivo and will elucidate the benefits of early (preventative) vs. late (interventional) CD33 knockdown which will inform potential future treatments of CD33-targeting therapeutics.

摘要小胶质细胞是脑的免疫细胞，是脑胶质细胞瘤的发病机制和进展中的关键细胞参与者。阿尔茨海默病（AD）。作为大脑的免疫细胞，小胶质细胞是主要参与的细胞类型在蛋白质聚集体如淀粉样蛋白B（Ab）的吞噬中，其聚集形成特征性的 AD中存在斑块。小胶质细胞吞噬能力的降低，结合促炎性表型，可能导致允许Ab斑块形成的脑环境。最近的全基因组相关研究已经确定了免疫细胞特异性基因CD 33的突变，其表达几乎专门针对大脑中的小胶质细胞，作为AD发展的风险因素。CD 33是Siglec的成员。受体家族，并且在检测唾液酸时具有免疫抑制作用。的表达降低 CD 33通过刺激吞噬作用和改变促炎性细胞因子来保护抗体斑块的形成。小胶质细胞中的表型。因此，CD 33代表了治疗和预防糖尿病的重要治疗靶点。 AD.然而，由于技术原因，尚未确定抗CD 33治疗的适当时间点。在AD转基因动物模型的脑中操纵CD 33的挑战。在这里，我们建议使用脑和小胶质细胞验证的方法，用于将CRISPR递送至脑以敲低CD 33的表达。在AD的转基因动物模型中疾病进展过程中的不同时间。我们预测疾病早期和晚期CD 33的下调将差异性地改变小胶质细胞对Ab的吞噬作用，斑块负荷，消除神经毒性，并改善记忆缺陷。此外，我们的目标是了解通过检查现有单细胞检测人类AD患者中小胶质细胞CD 33表达的异质性转录组学数据集。我们预测，CD 33减少的小胶质细胞将表现出吞噬作用，神经保护基因标记。我们预测这种基因标记在CD 33-high和CD 33-low中也是明显的。转基因AD小鼠的低小胶质细胞。最后，我们将测试唾液酸结合作为一种潜在的机制， CD 33调节Ab的吞噬作用。总的来说，这些研究将加强我们目前对CD 33如何改变体内小胶质细胞功能，并将阐明早期（预防性）与晚期（干预性）的益处 CD 33敲低，这将为CD 33靶向治疗剂的潜在未来治疗提供信息。