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Classical complement cascade initiating C1q protein within neurons in the aged rhesus macaque dorsolateral prefrontal cortex.
Journal of Neuroinflammation ( IF 9.3 ) Pub Date : 2020-01-06 , DOI: 10.1186/s12974-019-1683-1
Dibyadeep Datta 1 , Shannon N Leslie 2, 3 , Yury M Morozov 1 , Alvaro Duque 1 , Pasko Rakic 1 , Christopher H van Dyck 1, 2 , Angus C Nairn 2 , Amy F T Arnsten 1
Affiliation  

BACKGROUND Cognitive impairment in schizophrenia, aging, and Alzheimer's disease is associated with spine and synapse loss from the dorsolateral prefrontal cortex (dlPFC) layer III. Complement cascade signaling is critical in driving spine loss and disease pathogenesis. Complement signaling is initiated by C1q, which tags synapses for elimination. C1q is thought to be expressed predominately by microglia, but its expression in primate dlPFC has never been examined. The current study assayed C1q levels in aging primate dlPFC and rat medial PFC (mPFC) and used immunoelectron microscopy (immunoEM), immunoblotting, and co-immunoprecipitation (co-IP) to reveal the precise anatomical distribution and interactions of C1q. METHODS Age-related changes in C1q levels in rhesus macaque dlPFC and rat mPFC were examined using immunoblotting. High-spatial resolution immunoEM was used to interrogate the subcellular localization of C1q in aged macaque layer III dlPFC and aged rat layer III mPFC. co-IP techniques quantified protein-protein interactions for C1q and proteins associated with excitatory and inhibitory synapses in macaque dlPFC. RESULTS C1q levels were markedly increased in the aged macaque dlPFC. Ultrastructural localization found the expected C1q localization in glia, including those ensheathing synapses, but also revealed extensive localization within neurons. C1q was found near synapses, within terminals and in spines, but was also observed in dendrites, often near abnormal mitochondria. Similar analyses in aging rat mPFC corroborated the findings in rhesus macaques. C1q protein increasingly associated with PSD95 with age in macaque, consistent with its synaptic localization as evidenced by EM. CONCLUSIONS These findings reveal novel, intra-neuronal distribution patterns for C1q in the aging primate cortex, including evidence of C1q in dendrites. They suggest that age-related changes in the dlPFC may increase C1q expression and synaptic tagging for glial phagocytosis, a possible mechanism for age-related degeneration.

中文翻译:

经典的补体级联启动老年恒河猴猕猴背外侧前额叶皮层神经元内的C1q蛋白。

背景技术精神分裂症,衰老和阿尔茨海默氏病中的认知障碍与背外侧前额叶皮层(dlPFC)III层的脊柱和突触丧失有关。补体级联信号在驱动脊柱丢失和疾病发病机理中至关重要。补体信号由C1q启动,C1q标记突触以消除。C1q被认为主要由小胶质细胞表达,但从未在灵长类动物dlPFC中表达。当前的研究分析了老化的灵长类动物dlPFC和大鼠内侧PFC(mPFC)中的C1q水平,并使用免疫电子显微镜(immunoEM),免疫印迹和免疫共沉淀(co-IP)揭示了C1q的精确解剖分布和相互作用。方法采用免疫印迹法检测猕猴dlPFC和大鼠mPFC中C1q水平的年龄相关变化。高空间分辨率immunoEM用于询问老化的猕猴层III dlPFC和老化的大鼠层III mPFC中C1q的亚细胞定位。co-IP技术量化了猕猴dlPFC中C1q以及与兴奋性和抑制性突触相关的蛋白质的蛋白质-蛋白质相互作用。结果在老化的猕猴dlPFC中,C1q水平显着增加。超微结构定位在胶质细胞中发现了预期的C1q定位,包括那些鞘突触,但也揭示了神经元内的广泛定位。C1q在突触附近,终末和棘突中发现,但在树突中也观察到,通常在异常线粒体附近。衰老大鼠mPFC中的类似分析证实了恒河猴的发现。随着猕猴年龄的增长,C1q蛋白与PSD95的相关性越来越高,符合EM证明的突触定位。结论这些发现揭示了老化的灵长类皮层中C1q的新型神经内分布模式,包括树突中C1q的证据。他们认为dlPFC中与年龄相关的变化可能会增加C1q表达和神经胶质吞噬作用的突触标记,这是与年龄相关的变性的一种可能机制。
更新日期:2020-01-07
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