An Hongliang, Gu Jianhong, Li Taiping
Department of Pharmacy, Nanjing Meishan Hospital, Nanjing, China.
Child Mental Health Research Center, Nanjing Brain Hospital Affiliated to Nanjing Medical University, Nanjing, China.
Brain Behav. 2025 Aug;15(8):e70797. doi: 10.1002/brb3.70797.
To identify potential druggable targets for Alzheimer's disease (AD) by analyzing circulating inflammatory proteins using Mendelian randomization (MR).
Two-sample MR analysis was employed to investigate the causal relationships between 91 circulating inflammatory proteins and AD. The primary MR method utilized was the inverse variance weighted (IVW) model, while the weighted median (WM) and MR-Egger models were applied for sensitivity analysis. To assess the heterogeneity of instrumental variables (IVs), Cochran's Q-test and I statistics were utilized. Additionally, ChEMBL and DGIdb databases with Bayesian colocalization analysis were consulted to identify potential druggable proteins.
MR analysis identified eight inflammatory proteins significantly associated with AD risk. Among these proteins, TNFB [odds ratio (OR): 1.06, 95% Confidence Interval (CI): 1.02-1.11, p = 8.77×10 ], TSLP (OR: 1.10, 95% CI: 1.01-1.19, p = 0.028), S100A12 (OR: 1.09, 95% CI: 1.01-1.18, p = 0.03), CD244 (OR: 1.07, 95% CI: 1.00-1.13, p = 0.036), and IL33 (OR: 1.08, 95% CI: 1.00 -1.17, p = 0.048) were identified as proteins associated with elevated AD risk. Conversely, three inflammatory proteins exhibited a protective effect against AD, including NRTN (OR: 0.91, 95% CI: 0.85-0.99; p = 0.019), CCL4 (OR: 0.95, 95% CI: 0.91-1.00, p = 0.029), and MMP1 (OR: 0.93, 95% CI: 0.87-1.00, p = 0.049). Notably, according to the gene-drug analysis, TSLP, S100A12, CD244, CCL4, and MMP1 were identified as druggable. Additionally, MMP1 (PP4 = 0.92) and CCL4 (PP4 = 0.87) in the prefrontal cortex had the strongest colocalization evidence (PP4 > 0.85), suggesting they could potentially serve as novel therapeutic targets for AD.
Integrative genetic analyses indicate that genetically determined circulating levels of TSLP, S100A12, CD244, CCL4, and MMP1 exert causal effects on AD risk. These findings nominate all five proteins as potential therapeutic targets, with MMP1 and CCL4 representing priority candidates warranting further mechanistic investigation and clinical validation.
通过孟德尔随机化（MR）分析循环炎症蛋白，以确定阿尔茨海默病（AD）潜在的可成药靶点。
采用两样本MR分析来研究91种循环炎症蛋白与AD之间的因果关系。主要使用的MR方法是逆方差加权（IVW）模型，同时应用加权中位数（WM）和MR-Egger模型进行敏感性分析。为评估工具变量（IVs）的异质性，使用了Cochran's Q检验和I统计量。此外，查阅了ChEMBL和DGIdb数据库并进行贝叶斯共定位分析，以识别潜在的可成药蛋白。
MR分析确定了8种与AD风险显著相关的炎症蛋白。在这些蛋白中，肿瘤坏死因子β（TNFB）[比值比（OR）：1.06，95%置信区间（CI）：1.02 - 1.11，p = 8.77×10⁻⁵]、胸腺基质淋巴细胞生成素（TSLP）（OR：1.10，95% CI：1.01 - 1.19，p = 0.028）、钙结合蛋白A12（S100A12）（OR：1.09，95% CI：1.01 - 1.18，p = 0.03）、2B4蛋白（CD244）（OR：1.07，95% CI：1.00 - 1.13，p = 0.036）和白细胞介素33（IL33）（OR：1.08，95% CI：1.00 - 1.17，p = 0.048）被确定为与AD风险升高相关的蛋白。相反，3种炎症蛋白对AD具有保护作用，包括神经营养因子（NRTN）（OR：0.91，95% CI：0.85 - 0.99；p = 0.019）、趋化因子4（CCL4）（OR：0.95，95% CI：0.91 - 1.00，p = 0.029）和基质金属蛋白酶1（MMP1）（OR：0.93，95% CI：0.87 - 1.00，p = 0.049）。值得注意的是，根据基因 - 药物分析，TSLP、S100A12、CD244、CCL4和MMP1被确定为可成药的。此外，前额叶皮质中的MMP1（PP4 = 0.92）和CCL4（PP4 = 0.87）具有最强的共定位证据（PP4 > 0.85），表明它们可能是AD潜在的新治疗靶点。
综合基因分析表明，遗传决定的TSLP、S100A12、CD244、CCL4和MMP1的循环水平对AD风险有因果影响。这些发现将所有这5种蛋白提名作为潜在的治疗靶点，其中MMP1和CCL4是优先候选者，值得进一步进行机制研究和临床验证。
