Synapse loss associated with abnormal PrP precedes neuronal degeneration in the scrapie-infected murine hippocampus
Synapse loss associated with abnormal PrP precedes neuronal degeneration in the scrapie-infected murine hippocampus
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DOI：
10.1046/j.1365-2990.2000.00216.x
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发表时间：
2000-02-01
影响因子：
5
通讯作者：
Fraser, JR
中科院分区：
文献类型：
--
作者：
Jeffrey, M;Halliday, WG;Fraser, JR
在一个伴有严重海马锥体细胞丢失的小鼠痒病模型中，对神经元、突触和轴突终末的数量进行了量化。在该模型中，感染后226天（dpi）明显出现临床痒病症状，约250 dpi死亡。在丘脑以及CA1锥体细胞层内的稀疏病灶中，在70 dpi（潜伏期（IP）的28%）首次观察到疾病特异性的朊蛋白（PrP）积聚。到98 dpi（39% IP）时，在放射层观察到PrP，并且在后期整个海马的各个层面都能发现。在CA1放射层的超微结构水平上，使用无偏立体学方法——分割器分析发现，从84 dpi（34% IP）起简单突触数量减少，从98 dpi（42% IP）起穿孔突触数量减少。从98 dpi（39% IP）起发现轴突终末变性。从180 dpi（72% IP）起在CA1检测到神经元丢失。结果表明，ME7感染小鼠海马中的基本病变与CA1锥体细胞释放PrP有关，这扰乱了突触功能并导致轴突终末前体变性，随后包括神经元丢失在内的病理变化是这种初始损伤的后遗症。
Numbers of neurones, synapses and axon terminals were quantified in a murine scrapie model with severe hippocampal pyramidal cell loss, in which definite clinical scrapie is evident from 226 days post-infection (dpi) and death occurs around 250 dpi. Disease-specific PrP accumulations were first seen at 70 dpi (28% of the incubation period (IP)) in thalamus and as sparse foci within the stratum pyramidale of CA1. By 98 dpi (39% IP), PrP was seen in the stratum radiatum and was found at later stages throughout all levels of the hippocampus. At the ultrastructural level in the stratum radiatum of CA1, a decrease in the numbers of simple synapses from 84 dpi (34% IP) and in perforated synapses from 98 dpi (42% IP) was found using an unbiased stereological method, the disector analysis. Degeneration of axon terminals was found from 98 dpi (39% IP) onwards. Neuronal loss was detected in CA1 from 180 dpi (72% IP). The results suggest that the fundamental lesion in the hippocampus of ME7-infected mice is associated with PrP release from CA1 pyramidal neurones, which perturbs synaptic function and leads to degeneration of preterminal axons, and that subsequent pathological changes including neurone loss are sequelae to this initial insult.