Kitamura Hiroyuki W, Hamanaka Hiroki, Watanabe Masahiko, Wada Koji, Yamazaki Chiharu, Fujita Shinobu C, Manabe Toshiya, Nukina Nobuyuki
Laboratory for Neurodegeneration Signal, RIKEN Brain Science Institute, Saitama 351-0198, Japan.
Neurosci Lett. 2004 Oct 21;369(3):173-8. doi: 10.1016/j.neulet.2004.07.084.
Human apolipoprotein E (apoE) comprises three isoforms, apoE2, apoE3 and apoE4, and apoE4 has been reported as a risk factor of Alzheimer's disease (AD). One of the clinical symptoms of AD is disorder of memory that has been suggested to be related with synaptic plasticity such as long-term potentiation (LTP). Here, we show the enhancement of hippocampal LTP at younger age in knock-in mice lacking mouse apoE, but instead expressing human apoE4. The enhancement of LTP in apoE4 knock-in mice is age-dependent, and it disappears in adult apoE4 knock-in mice. In apoE3 knock-in mice LTP is unaltered, thus human apoE4, but not apoE3, specifically modulates synaptic plasticity at younger age. Since basal synaptic transmission and distribution of glutamate receptors, as well as presynaptic functions, are intact in apoE4 knock-in mice, postsynaptic functional modification of LTP through lipid homeostasis is suggested. ApoE4 knock-in mice would be a useful animal model of human apoE4 carriers, and our finding that LTP is enhanced in younger apoE4 knock-in mice is in accord with the previous report showing higher intelligence in young human apoE4 carriers.
人类载脂蛋白E（apoE）包含三种异构体，即apoE2、apoE3和apoE4，且据报道apoE4是阿尔茨海默病（AD）的一个风险因素。AD的临床症状之一是记忆障碍，这被认为与诸如长时程增强（LTP）等突触可塑性有关。在此，我们发现，在缺乏小鼠apoE但表达人类apoE4的基因敲入小鼠中，幼年时海马体LTP增强。apoE4基因敲入小鼠中LTP的增强具有年龄依赖性，在成年apoE4基因敲入小鼠中消失。在apoE3基因敲入小鼠中LTP未改变，因此，人类apoE4而非apoE3在幼年时特异性调节突触可塑性。由于apoE4基因敲入小鼠的基础突触传递、谷氨酸受体分布以及突触前功能均完好无损，提示LTP通过脂质稳态进行突触后功能修饰。apoE4基因敲入小鼠将是人类apoE4携带者的一种有用动物模型，并且我们发现幼年apoE4基因敲入小鼠中LTP增强，这与之前显示年轻人类apoE4携带者具有更高智力的报道一致。
