Tenner Andrea J, Fonseca Maria I
Department of Molecular Biology, Center for Immunology, University of California, Irvine, CA 92697, USA.
Adv Exp Med Biol. 2006;586:153-76. doi: 10.1007/0-387-34134-X_11.
A role for the complement cascade in AD neuropathology was hypothesized over a decade ago, and the results of a significant number of in vitro studies are consistent with the involvement of this pathway in AD pathogenesis (reviewed in). Since C1q is colocalized with thioflavine-positive plaques and the C5b-9 complement membrane attack complex is detected in AD brain at autopsy, it is reasonable to hypothesize that complement activation has a role in the manifestation of AD either by its lytic capacity or as a trigger of glial infiltration and initiation of potentially damaging inflammation. The observed diminished glial activation and reduced loss of neuronal integrity in a murine model overexpressing mutant human APP but lacking the ability to activate the classical complement cascade provide the first direct evidence for a detrimental role of C1q, and presumably activation of the classical complement pathway in an animal model of AD. Research is now focused on generating mouse models that more closely mimic the human disease, so that the role of complement activation and inflammation on the behavioral/learning and memory dysfunction that occurs in this disease can be assessed. In addition, candidate therapies such as targeted inhibition of complement activation will need to be tested in these animal models as a step toward treatment of humans with the disease. However, it is important that the potential for a protective effect of C1q early on in disease progression should not be overlooked. Rather, strategies that enhance or mimic the protective effects of C1q as well as strategies that inhibit the detrimental processes should be fully investigated.
十多年前就有人提出补体级联反应在阿尔茨海默病神经病理学中发挥作用，大量体外研究结果与该途径参与阿尔茨海默病发病机制一致（相关综述见[具体文献]）。由于在尸检时发现C1q与硫黄素阳性斑块共定位，且在阿尔茨海默病患者大脑中检测到C5b - 9补体膜攻击复合物，因此有理由推测补体激活通过其溶解能力或作为胶质细胞浸润的触发因素以及潜在破坏性炎症的起始因素，在阿尔茨海默病的表现中发挥作用。在一个过表达突变型人类APP但缺乏激活经典补体级联反应能力的小鼠模型中，观察到胶质细胞激活减少和神经元完整性丧失减少，这为C1q的有害作用以及推测经典补体途径在阿尔茨海默病动物模型中的激活提供了首个直接证据。目前的研究重点是建立更接近人类疾病的小鼠模型，以便评估补体激活和炎症对该疾病中出现的行为/学习和记忆功能障碍的作用。此外，作为朝着治疗人类该疾病迈进的一步，需要在这些动物模型中测试诸如靶向抑制补体激活等候选疗法。然而，重要的是不应忽视C1q在疾病进展早期可能具有的保护作用。相反，应充分研究增强或模拟C1q保护作用的策略以及抑制有害过程的策略。
