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 将遗传学转化为药理学策略的关键障碍。A多态性 在多个全基因组关联研究中，CD 33附近已被确定为AD风险因素， 包括最近的大型研究。CD 33是唾液酸结合蛋白的一个成员。 免疫球蛋白型凝集素（SIGLEC）家族，其与先天免疫调节有关。 我们和其他人发现，CD 33的表达仅限于大脑中的小胶质细胞。 此外，AD保护性等位基因的作用是增加CD 33亚型缺乏外显子2（D2-CD 33）， 全长CD 33的费用。由于外显子2编码唾液酸配体结合结构域，我们 将外显子2缺失与AD风险降低相关的发现解释为 功能性CD 33的减少及其相关的免疫抑制是AD保护性的。 然而，这种解释需要重新考虑，因为我们最近发现，4 bp的CD 33 消除CD 33的基因缺失与AD风险无关。总之，我们 目前提出了一种模型，其中D2-CD 33同种型代表功能变体的增益， 降低AD风险，因为（i）降低AD风险的遗传多态性增加D2-CD 33， 但（ii）基本上缺失细胞表面CD 33的CD 33插入缺失 不影响AD风险。为了检验这个模型，我们提出了以下具体目标。具体 目的1：评价CD 33相关基因表达的变化是否可以补偿CD 33 缺陷具体目的2：在以下条件下确定D2-CD 33亚细胞定位： 生理性D2-CD 33表达。具体目标3：比较CD 33和D2-CD 33相互作用组。 具体目标4：比较CD 33和D2-CD 33对细胞功能的影响， 小胶质细胞这些研究的成功完成将确定D2-CD 33为主要的 在这个位点的药理学目标，以降低AD的风险。