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Role of complement systems in IVIG mediated attenuation of cognitive deterioration in Alzheimer's disease

机译:补体系统在IVIG介导的阿尔茨海默氏病认知衰退衰减中的作用

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Human intravenous immunoglobulin (IVIG) has been indicated as a potential therapy for autoimmune neurological disorders, as well as in many neurodegenerative diseases, with various underlying therapeutic mechanisms such as regulation of T-cell trafficking, cytokines, Fc receptor blocking, and interruption of complement activation cascade. In Alzheimer's disease (AD), IVIG presents naturally occurring antibodies against amyloid-beta (Aβ) aggregation, thus IVIG immunotherapy may increase the clearance of Aβ and protect brain function. Recently, we and others reported that besides Aβ clearance, IVIG specifically regulates the levels of complement-derived anaphylatoxins, such as C5a and C3, which play an important role in the regulation of AMPA and NMDA receptor expression in the brain and further upregulate the AMPA-PKA-CREB signaling pathway and synaptic function in AD mouse models. Since down-regulation of complement components has been linked with deficits of cognitive function in age-related dementia following the decline of innate immunity during aging, the IVIG immunotherapy could be an attractive novel AD therapeutic through its local regulation of C3, C5a component levels in brain.
机译:人静脉免疫球蛋白(IVIG)已被证明是一种针对自身免疫性神经疾病以及许多神经退行性疾病的潜在疗法,具有多种潜在的治疗机制,例如调节T细胞运输,细胞因子,Fc受体阻断和补体中断激活级联。在阿尔茨海默氏病(AD)中,IVIG呈现天然存在的抗β-淀粉样蛋白(Aβ)聚集的抗体,因此IVIG免疫疗法可能会增加Aβ的清除率并保护大脑功能。最近,我们和其他人报道说,IVIG除了能清除Aβ外,还可以特异性调节补体衍生的过敏毒素(如C5a和C3)的水平,它们在调节AMPA和NMDA受体在大脑中的表达中起着重要作用,并进一步上调AMPA -PKA-CREB信号通路和AD小鼠模型中的突触功能。由于在衰老过程中先天免疫力下降后,补体成分的下调与年龄相关性痴呆的认知功能缺陷有关,因此IVIG免疫疗法通过局部调节C3,C5a的水平可能是一种有吸引力的新型AD治疗药物。脑。

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