Alzheimer's disease (AD), the most predominant type of dementia, is characterized by progressive cognitive impairment and currently has no effective treatment. While the exact cause of AD remains unclear, our previous genetics study identified an IL1RL1 variant that protects against AD risk and other AD-associated endophenotypes in female APOE-ε4 carriers. Therefore, it is important to investigate the molecular and cellular mechanisms underlying the protective effects of this IL1RL1 genetic variant. In this study, I first identified that endothelial cells are the major cell type that express soluble ST2 (sST2) in the human brain by performing single-nucleus RNA sequencing analysis. The IL1RL1 genetic variant regulated the gene expression of sST2 in endothelial cells in a dose-dependent...[ Read more ]

Alzheimer's disease (AD), the most predominant type of dementia, is characterized by progressive cognitive impairment and currently has no effective treatment. While the exact cause of AD remains unclear, our previous genetics study identified an IL1RL1 variant that protects against AD risk and other AD-associated endophenotypes in female APOE-ε4 carriers. Therefore, it is important to investigate the molecular and cellular mechanisms underlying the protective effects of this IL1RL1 genetic variant. In this study, I first identified that endothelial cells are the major cell type that express soluble ST2 (sST2) in the human brain by performing single-nucleus RNA sequencing analysis. The IL1RL1 genetic variant regulated the gene expression of sST2 in endothelial cells in a dose-dependent manner. In addition, transcriptomic analysis revealed that endothelial cells from the brains of patients with AD exhibited an angiogenic gene signature. Meanwhile, this transcriptomic profile was absent in patients with AD carrying the IL1RL1 genetic variant. To elucidate the roles of the IL1RL1 genetic variant in sST2 gene expression and endothelial functions, genomic deletion of the region harboring the variant was performed in cultured endothelial cells using a CRISPR/Cas9-based approach. I found that the IL1RL1 variant-harboring region is an essential regulator of the gene expression of sST2 as well as tube formation in endothelial cells. Interestingly, knockdown of sST2 in endothelial cells resulted in defective tube formation, phenocopying the result of deleting the IL1RL1 variant-harboring regions. This suggests that the IL1RL1 genetic variant modulates endothelial functions through the regulation of endothelial sST2 expression. Moreover, on the basis of the association analysis of plasma sST2 level in patients with AD and drug use, I examined which drugs can potentially regulate the expression and secretion of sST2 in endothelial cells. Accordingly, noradrenaline treatment significantly increased sST2 level, whereas blockade of adrenergic receptors reduced the sST2 level in endothelial cells, suggesting that adrenergic receptor signaling plays a key role in regulating sST2 levels. In summary, the results of my study demonstrate that the IL1RL1 genetic variant protects against the dysregulated endothelial functions observed in AD and that targeted lowering of the circulating sST2 level by adrenergic drugs has therapeutic potential for AD.