Hereditary deficiencies in complement C5 are associated with intensified neurodegenerative responses that implicate new roles for the C-system in neuronal and astrocytic functions
Hereditary deficiencies in complement C5 are associated with intensified neurodegenerative responses that implicate new roles for the C-system in neuronal and astrocytic functions
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DOI：
10.1006/nbdi.1996.0020
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发表时间：
1996-01-01
影响因子：
6.1
通讯作者：
Finch, CE
中科院分区：
文献类型：
--
作者：
Pasinetti, GM;Tocco, G;Finch, CE
通过携带C5基因移码突变的近交系小鼠，探索了补体(C)系统在正常和受损大脑中的可能作用。采用一对同源基因：C57BL/10J供体株的C5(C5(+))D2/nSnJ株和C5缺陷型(C5(-))D2/oSnJ株和C5缺陷型DBA/2J供体株的Hc0等位基因进行比较。在兴奋性毒素海人酸(KA)刺激下，C5(-)小鼠海马锥体神经元死亡较多，星形胶质细胞mRNAs(GFAP、apoE、apoJ)诱导较多。在未损伤的小鼠的原代星形胶质细胞培养中，炎性刺激(LPS)导致C5(-)小鼠产生更多的IL-6和TNF。这些对KA和内毒素的增强反应表明，遗传性C5缺陷改变了神经元和星形胶质细胞对神经退行性刺激的反应。此外，未损伤的C5(-)小鼠的EPSP幅度的NMDA成分的输入输出斜率较小，但增强了钙依赖的AMPA结合。因此，C5缺陷也改变了与突触可塑性有关的谷氨酸能神经传递的基本特性，这些发现也与C系统在阿尔茨海默病(AD)中的作用有关。在选择作为转基因宿主的菌株以及对正常和病理大脑功能进行遗传分析时，也可以考虑C5缺陷。在最近的AD转基因研究中，C5(-)宿主显示出更大的神经退行性变，这与目前的数据一致。C5缺乏的这些多效性关联表明C系统在神经退行性变中的作用，但也在正常的神经功能中发挥作用。(C)1996年学术出版社。
Possible roles of the complement (C) system in the normal and injured brain were explored with inbred mice that carried a frameshift mutation in the C5 gene. A congenic pair was used: the CS-sufficient (C5(+)) B10.D2/nSnJ strain with the functional allele (Hc1) from the C57BL/10J donor strain was compared with the C5-deficient (C5(-)) B10.D2/oSnJ with the Hc0 allele from the C5-deficient DBA/2J donor strain. In response to the excitotoxin kainic acid (KA), C5(-) mice had more hippocampal pyramidal neuron death and greater induction of astrocyte mRNAs (GFAP, apoE, apoJ). In primary astrocyte cultures from unlesioned mice, an inflammatory stimulus (LPS) caused greater production of IL-6 and TNF production in C5(-) mice. These enhanced responses to KA and LPS suggest that hereditary C5 deficits modify responses to neurodegenerative stimuli of neurons and astrocytes. Moreover, unlesioned C5(-) mice had smaller input-output slopes for the NMDA component of the EPSP amplitude, but enhanced the Ca+2-dependent AMPA binding. Thus, C5 deficits also modify basal properties of glutamatergic neurotransmission that pertain to synaptic plasticity, These findings are also discussed in relation to roles of the C-system in Alzheimer disease (AD). C5 deficiencies may also be considered in the choice of strains as transgene hosts and for genetic analysis of normal and pathological brain functions. In recent transgenic studies for AD, C5(-) hosts showed greater neurodegeneration, consistent with the present data. These pleiotropic associations of C5 deficiency indicate roles for the C-system in neurodegeneration, but also in normal neural functions. (C) 1996 Academic Press, Inc.