Sanfilippo Cristina, Castrogiovanni Paola, Imbesi Rosa, Vecchio Michele, Sortino Martina, Musumeci Giuseppe, Vinciguerra Manlio, Di Rosa Michelino
Neurologic Unit, AOU "Policlinico-San Marco", Department of Medical, Surgical Sciences and Advanced Technologies, GF, Ingrassia, University of Catania, Via Santa Sofia n.78, Catania, 95100, Sicily, Italy.
Department of Biomedical and Biotechnological Sciences, Human Anatomy and Histology Section, School of Medicine, University of Catania, Catania, Italy.
Metab Brain Dis. 2025 Jan 4;40(1):83. doi: 10.1007/s11011-024-01523-4.
SERPINA3, a serine protease inhibitor, is strongly associated with neuroinflammation, a typical condition of AD. Its expression is linked to microglial and astrocytic markers, suggesting it plays a significant role in modulating neuroinflammatory responses. In this study, we examined the SERPINA3 expression levels, along with CHI3L1, in various brain regions of AD patients and non-demented healthy controls (NDHC). Nineteen microarray datasets were analyzed, with brain samples stratified by sex and age from areas including the prefrontal cortex, occipital lobe, and cerebellum. Results showed that SERPINA3 was significantly highly expressed in AD patients compared to NDHCs only in males. Sex-specific differences were observed only in NDHCs, where females had higher SERPINA3 levels than males. ROC analysis suggested that SERPINA3 could be a strong marker for distinguishing AD in males but not females. In NDHCs, SERPINA3 expression correlated more strongly with age than in AD patients. In brain regions, SERPINA3 expression in NDHC females was higher across multiple areas, while in AD patients, this difference was limited to the prefrontal cortex. The most significant differences between NDHC and AD patients were found in the occipital and prefrontal regions. Furthermore, we identified a potential nuclear localization for SERPINA3, supported by immunohistochemistry analysis from The Human Protein Atlas. Correlation with neuropathological traits, including Clinical Dementia Rating (CDR) and Braak Neurofibrillary Tangle Score, showed positive significant associations between SERPINA3 and CDR in AD patients. Performing a docking analysis, we revealed an interaction region between SERPINA3 and CHI3L1 proteins, suggesting a potential role in AD. Tissue transcriptomic deconvolution analysis indicated a significant overlap between SERPINA3 expression and microglial/astrocytic signatures, suggesting that SERPINA3 plays a key role in modulating neuroinflammation in AD.
丝氨酸蛋白酶抑制剂SERPINA3与神经炎症密切相关，而神经炎症是阿尔茨海默病（AD）的典型症状。其表达与小胶质细胞和星形胶质细胞标志物相关，表明它在调节神经炎症反应中起重要作用。在本研究中，我们检测了AD患者和非痴呆健康对照（NDHC）不同脑区中SERPINA3以及CHI3L1的表达水平。分析了19个微阵列数据集，脑样本按性别和年龄分层，来自前额叶皮质、枕叶和小脑等区域。结果显示，仅在男性AD患者中，SERPINA3的表达显著高于NDHC。仅在NDHC中观察到性别特异性差异，其中女性的SERPINA3水平高于男性。ROC分析表明，SERPINA3可能是区分男性AD的有力标志物，但对女性则不然。在NDHC中，SERPINA3表达与年龄的相关性比AD患者更强。在脑区中，NDHC女性的SERPINA3表达在多个区域更高，而在AD患者中，这种差异仅限于前额叶皮质。NDHC和AD患者之间最显著的差异出现在枕叶和前额叶区域。此外，我们通过人类蛋白质图谱的免疫组织化学分析确定了SERPINA3的潜在核定位。与神经病理学特征（包括临床痴呆评定量表（CDR）和Braak神经原纤维缠结评分）的相关性显示，AD患者中SERPINA3与CDR之间存在显著正相关。通过对接分析，我们揭示了SERPINA3和CHI3L1蛋白之间的相互作用区域，表明其在AD中可能发挥作用。组织转录组反卷积分析表明，SERPINA3表达与小胶质细胞/星形胶质细胞特征之间存在显著重叠，表明SERPINA3在调节AD神经炎症中起关键作用。
