Department of Neurology, Columbia University Irving Medical Center, New York, NY 10032, USA.
Division of Translational Neurobiology, Department of Neurology, Columbia University Irving Medical Center, New York, NY 10032, USA.
Genes (Basel). 2024 Sep 13;15(9):1204. doi: 10.3390/genes15091204.
Large-scale genetic studies have identified numerous genetic risk factors that suggest a central role for innate immune cells in susceptibility to Alzheimer's disease (AD). CD33, an immunomodulatory transmembrane sialic acid binding protein expressed on myeloid cells, was identified as one such genetic risk factor associated with Alzheimer's disease. Several studies explored the molecular outcomes of genetic variation at the locus. It has been determined that the risk variant associated with AD increases the expression of the large isoform of CD33 (CD33M) in innate immune cells and alters its biological functions. CD33 is thought to signal via the interaction of its ITIM motif and the protein tyrosine phosphatase, SHP-1. Here, we utilize different molecular and computational approaches to investigate how AD-associated genetic variation in CD33 affects its interaction with SHP-1 in human microglia and microglia-like cells. Our findings demonstrate a genotype-dependent interaction between CD33 and SHP-1, which may functionally contribute to the AD risk associated with this variant. We also found that (SHP-1) gene-gene interactions impact AD-related traits, while (SHP-2) interactions do not.
大规模的遗传研究已经确定了许多遗传风险因素，这些因素表明先天免疫细胞在阿尔茨海默病（AD）易感性中起着核心作用。CD33 是一种表达在髓样细胞上的免疫调节跨膜唾液酸结合蛋白，被确定为与 AD 相关的遗传风险因素之一。有几项研究探讨了 基因座遗传变异的分子结果。已经确定与 AD 相关的风险变体增加了先天免疫细胞中 CD33 大异构体（CD33M）的表达，并改变了其生物学功能。CD33 被认为通过其 ITIM 基序和蛋白酪氨酸磷酸酶 SHP-1 的相互作用来传递信号。在这里，我们利用不同的分子和计算方法来研究 AD 相关的 CD33 遗传变异如何影响其与人类小神经胶质细胞和小神经胶质样细胞中的 SHP-1 的相互作用。我们的研究结果表明，CD33 和 SHP-1 之间存在基因型依赖性相互作用，这可能对该变体与 AD 风险相关的功能有贡献。我们还发现，（SHP-1）基因-基因相互作用影响与 AD 相关的特征，而 （SHP-2）相互作用则没有。
