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

阐明遗传学影响阿尔茨海默病(AD)风险的机制是 将遗传学转化为药理学策略方面取得进展的关键障碍。A多态 在多基因组范围的关联研究中，NEAR CD33已被确定为AD的危险因素， 包括非常新的、非常大的研究。CD33是唾液酸结合的一员 免疫球蛋白型凝集素(Siglec)家族，与天然免疫调节有关。 我们和其他人发现，CD33的表达仅限于大脑中的小胶质细胞。 此外，AD保护等位基因增加了缺失外显子2的CD33亚型(D2-CD33)。 全长CD33的花费。由于外显子2编码唾液酸配体结合域，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CD33的减少及其相关的免疫抑制是AD保护作用的结果。 然而，这种解释需要重新考虑，因为我们最近发现，一个4个BP的CD33 取消CD33的基因缺失与AD风险无关。总而言之，我们 目前提出了一个模型，其中D2-CD33异构体代表函数变量T0的增益 降低AD风险是因为(I)降低AD风险的基因多态增加了D2-CD33在 全长CD33的花费，但(Ii)实质上删除细胞表面CD33的CD33插入 不影响AD风险。为了测试该模型，我们提出了以下具体目标。特定的 目的1：评估CD33相关基因表达的变化是否可以补偿CD33 缺乏症。特定目标2：确定D2-CD33的亚细胞定位 生理性D2-CD33的表达。具体目标3：比较CD33和D2-CD33的相互作用。 具体目标4：比较CD33和D2-CD33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-CD33是主要的 此基因座的药物靶点可降低AD风险。

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.