How does D2-CD33 reduce Alzheimer's disease risk?

D2-CD33 如何降低阿尔茨海默病风险？

• 批准号: 10038417
• 负责人: Steven Estus
• 金额: $ 42.08万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10038417
• 关键词: Alleles; Alzheimer' s Disease; Alzheimer' s disease risk; Antibodies; Binding; Binding Proteins; Brain; Cell Line; Cell physiology; Cell surface; Cells; Clustered Regularly Interspaced Short Palindromic Repeats; Data; Exons; Extracellular Domain; Family; Financial compensation; Gene Expression; Genes; Genetic; Genetic Polymorphism; ITIM; Immunoglobulins; Immunosuppression; Lectin; Length; Ligand Binding Domain; Link; Location; Logic; Mediating; Microglia; Modeling; Molecular Genetics; Natural Immunity; PTPN6 gene; Peptides; Phagocytes; Phagocytosis; Pharmacology; Phosphopeptides; Physiological; Production; Protein Analysis; Protein Isoforms; Proteins; Proteomics; Proxy; RNA Decay; Regulation; Reporting; Risk Factors; Sialic Acids; Signal Transduction; Signaling Protein; Single Nucleotide Polymorphism; Small Interfering RNA; Terminator Codon; Testing; Translating; Variant; Viral; Work; cytokine; gain of function; genetic risk factor; genome wide association study; genomic locus; high risk; immune activation; insertion/deletion mutation; loss of function; member; novel; peroxisome; premature; protective allele

Elucidating the mechanism whereby genetics impact the risk of Alzheimer’s disease (AD) is a critical barrier to progress in translating genetics to pharmacologic strategies. A polymorphism near CD33 has been identified as an AD risk factor in multiple genome wide association studies, including very recent, very large studies. CD33 is a member of the sialic acid-binding immunoglobulin-type lectin (SIGLEC) family which is linked to regulation of innate immunity. We and others have found that CD33 expression is restricted to microglia in the brain. Moreover, the AD-protective allele acts to increase a CD33 isoform lacking exon 2 (D2-CD33) at the expense of full-length CD33. Since exon 2 encodes the sialic acid ligand binding domain, we interpreted the finding that loss of exon 2 was associated with decreased AD risk as meaning that a decrease in functional CD33 and its associated immune suppression was AD-protective. However, this interpretation needs to be reconsidered given our recent finding that a 4 bp CD33 genetic deletion, which abrogates CD33, is not associated with AD risk. In summary, we currently propose a model wherein the D2-CD33 isoform represents a gain of function variant to reduce AD risk because (i) a genetic polymorphism that reduces AD risk increases D2-CD33 at the expense of “full-length” CD33 but (ii) a CD33 indel that essentially deletes cell surface CD33 does not affect AD risk. To test this model, we propose the following Specific Aims. Specific Aim 1: Evaluate whether changes in CD33-related gene expression may compensate for CD33 deficiency. Specific Aim 2: Determine D2-CD33 subcellular localization under conditions of physiologic D2-CD33 expression. Specific Aim 3: Compare CD33 and D2-CD33 interactomes. Specific Aim 4: Compare impact of CD33 and D2-CD33 on cellular functions critical to microglia. Successful completion of these studies will pinpoint D2-CD33 as the primary pharmacologic target in this locus to reduce AD risk.

阐明遗传学影响阿尔茨海默病 (AD) 风险的机制是一个重要的课题 将遗传学转化为药理学策略的关键障碍。多态性 在多项全基因组关联研究中，near CD33 已被确定为 AD 危险因素， 包括最近的、非常大的研究。 CD33 是唾液酸结合蛋白的成员 免疫球蛋白型凝集素 (SIGLEC) 家族与先天免疫的调节有关。 我们和其他人发现 CD33 表达仅限于大脑中的小胶质细胞。 此外，AD 保护性等位基因可增加缺少外显子 2 (D2-CD33) 的 CD33 亚型 全长 CD33 的费用。由于外显子 2 编码唾液酸配体结合域，我们 将外显子 2 丢失与 AD 风险降低相关的发现解释为意义 功能性 CD33 的减少及其相关的免疫抑制具有 AD 保护作用。 然而，鉴于我们最近发现 4 bp CD33 基因缺失会消除 CD33，与 AD 风险无关。综上所述，我们 目前提出了一个模型，其中 D2-CD33 同工型代表功能变体的增益 降低 AD 风险，因为 (i) 降低 AD 风险的基因多态性会增加 D2-CD33 “全长”CD33 的代价，但 (ii) CD33 插入缺失基本上删除了细胞表面 CD33 不影响 AD 风险。为了测试这个模型，我们提出以下具体目标。具体的 目标 1：评估 CD33 相关基因表达的变化是否可以补偿 CD33 不足。具体目标 2：确定 D2-CD33 在以下条件下的亚细胞定位 生理 D2-CD33 表达。具体目标 3：比较 CD33 和 D2-CD33 相互作用组。 具体目标 4：比较 CD33 和 D2-CD33 对关键细胞功能的影响 小胶质细胞。这些研究的成功完成将确定 D2-CD33 是主要的 该位点的药理学目标可降低 AD 风险。