Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Vic, Australia.
Analytical Chemistry, Faculty of Science and Technology, University of Canberra, Canberra, ACT, Australia.
J Neurochem. 2021 Mar;156(6):979-987. doi: 10.1111/jnc.15114. Epub 2020 Jul 20.
Glutaminyl cyclases (QC) catalyze the formation of neurotoxic pGlu-modified amyloid-β peptides found in the brains of people with Alzheimer's disease (AD). Reports of several-fold increases in soluble QC (sQC) expression in the brain and peripheral circulation of AD individuals has prompted the development of QC inhibitors as potential AD therapeutics. There is, however, a lack of standardized quantitative data on QC expression in human tissues, precluding inter-laboratory comparison and validation. We tested the hypothesis that QC is elevated in AD tissues by quantifying levels of sQC protein and activity in post-mortem brain tissues from AD and age-matched control individuals. We found a modest but statistically significant increase in sQC protein, which paralleled a similar increase in enzyme activity. In plasma samples sourced from the Australian Imaging, Biomarker and Lifestyle study we determined that QC activity was not different between the AD and control group, though a modest increase was observed in female AD individuals compared to controls. Plasma QC activity was further correlated with levels of circulating monocytes in AD individuals. These data provide quantitative evidence that alterations in QC expression are associated with AD pathology.
谷氨酰胺环化酶 (QC) 催化形成存在于阿尔茨海默病 (AD) 患者大脑中的神经毒性 pGlu 修饰的淀粉样β肽。有报道称，AD 患者大脑和外周循环中可溶性 QC (sQC) 的表达增加了几倍，这促使人们开发 QC 抑制剂作为潜在的 AD 治疗药物。然而，由于缺乏人类组织中 QC 表达的标准化定量数据，因此无法进行实验室间的比较和验证。我们通过定量检测 AD 和年龄匹配的对照组尸检脑组织中的 sQC 蛋白和活性，检验了 QC 在 AD 组织中升高的假设。我们发现 sQC 蛋白水平略有但统计学上显著增加，与酶活性的类似增加平行。在源自澳大利亚成像、生物标志物和生活方式研究的血浆样本中，我们确定 AD 和对照组之间的 QC 活性没有差异，尽管与对照组相比，女性 AD 个体的 QC 活性略有增加。血浆 QC 活性与 AD 个体循环单核细胞的水平进一步相关。这些数据提供了定量证据，表明 QC 表达的改变与 AD 病理有关。
