Nimmo Jacqui, Keat Samuel, De Muynck Louis, Morgan B Paul
UK Dementia Research Institute Cardiff, Cardiff University, Cardiff, UK.
Janssen Research & Development, Janssen Pharmaceutica NV, a Johnson & Johnson Company, Beerse, Belgium.
Brain Pathol. 2025 Nov;35(6):e70017. doi: 10.1111/bpa.70017. Epub 2025 May 26.
Dysregulation of the complement system plays an important role in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD). In post-mortem AD brains, complement is deposited in and around amyloid plaques, and peri-plaque complement activation drives synapse loss in AD mouse models. Studies to date have focused on amyloid pathology; however, aggregated tau is also involved in neuronal loss in AD. Primary tauopathies are characterised by tau pathology in the absence of amyloid. The role of complement in human tauopathies remains largely unexplored. Here, we address this knowledge gap by assessing complement activation in human tauopathy brains using immunohistochemistry and well-characterised detection tools. Post-mortem pre-frontal cortex was obtained from three tauopathy subtypes, Pick's disease (PiD), globular glial tauopathy (GGT) and corticobasal degeneration (CBD) (3-5 cases each). C1q and the complement activation markers iC3b and terminal complement complex (TCC) were assessed by immunohistochemistry and were elevated in all tauopathy cases compared to controls, with C1q and C3b/iC3b deposition particularly prominent on neurons, demonstrating complement activation on these cells. TCC deposits were present on and adjacent neurons in all tauopathy brains examined and were significantly increased compared to controls in CBD and GGT. Uniquely in GGT, abundant deposition of C3b/iC3b on myelin was also observed, implicating complement in GGT-associated demyelination. To validate these findings, complement proteins (C1q, C3, factor B), regulators (factor I, clusterin) and activation products (Ba, C3b/iC3b, and TCC) were measured in brain homogenates by ELISA, revealing significant elevation in C3b/iC3b, Ba, and FI in CBD and GGT cases compared to controls. Together, our data demonstrate complement activation on and adjacent neurons in post-mortem brains from all tauopathy subtypes.
补体系统失调在包括阿尔茨海默病（AD）在内的神经退行性疾病发病机制中起重要作用。在AD患者的尸检大脑中，补体沉积在淀粉样斑块及其周围，且斑块周围的补体激活会导致AD小鼠模型中的突触丢失。迄今为止的研究主要集中在淀粉样病变上；然而，聚集的tau蛋白也与AD中的神经元丢失有关。原发性tau蛋白病的特征是不存在淀粉样病变的tau蛋白病理。补体在人类tau蛋白病中的作用在很大程度上仍未得到探索。在这里，我们通过使用免疫组织化学和特征明确的检测工具评估人类tau蛋白病大脑中的补体激活来填补这一知识空白。从三种tau蛋白病亚型，即匹克病（PiD）、球状胶质tau蛋白病（GGT）和皮质基底节变性（CBD）（每种3 - 5例）中获取尸检前额叶皮质。通过免疫组织化学评估C1q以及补体激活标志物iC3b和末端补体复合物（TCC），与对照组相比，所有tau蛋白病病例中这些指标均升高，C1q和C3b/iC3b在神经元上的沉积尤为突出，表明这些细胞上存在补体激活。在所检查的所有tau蛋白病大脑中，TCC沉积物存在于神经元及其附近，与对照组相比，CBD和GGT中的TCC沉积物显著增加。在GGT中独特的是，还观察到C3b/iC3b在髓鞘上大量沉积，这表明补体与GGT相关的脱髓鞘有关。为了验证这些发现，通过酶联免疫吸附测定（ELISA）在脑匀浆中测量补体蛋白（C1q、C3、B因子）、调节因子（I因子、簇集蛋白）和激活产物（Ba、C3b/iC3b和TCC），结果显示与对照组相比，CBD和GGT病例中的C3b/iC3b、Ba和FI显著升高。总之，我们的数据表明在所有tau蛋白病亚型的尸检大脑中，神经元及其附近存在补体激活。
