Hippocampal overexpression of Down syndrome cell adhesion molecule in amyloid precursor protein transgenic mice

Down syndrome cell adhesion molecule (DSCAM) is located within the Down syndrome critical region of chromosome 21. DSCAM is a broadly expressed neurodevelopmental protein involved in synaptogenesis, neurite outgrowth, and axon guidance. We previously demonstrated DSCAM overexpression in the cortex of amyloid precursor protein (APP) transgenic mice, suggesting possible regulatory interactions between APP and DSCAM. APP mice exhibit deficits in hippocampus-dependent learning and memory. In this preliminary study, we examined age-related changes in DSCAM expression within the hippocampus in 16 APP transgenic mice (1, 3, 6 and 12 months old). Hippocampus-dependent spatial memory was assessed in APP mice and age-matched wild type littermates (WTs) using the Morris water maze (MWM). The cellular distribution of hippocampal DSCAM and total expression at both mRNA and protein levels were measured by immunohistochemistry, qRT-PCR, and western blotting, respectively. APP mice exhibited spatial memory deficits in the MWM. Intense DSCAM immunoreactivity was observed in the dentate gyrus granule cell layer and hippocampal stratum pyramidale. Total hippocampal DSCAM mRNA and protein expression levels were substantially higher in APP mice than WTs at 1 and 3 months of age. Expression decreased with age in both groups but remained higher in APP mice. DSCAM is overexpressed in the hippocampus over the first 12 months of life in APP mice, but especially during maturation to adulthood. In conclusion, these results suggest an association between DSCAM and APP mice, which is characterized by neuropathology and behavioral deficits. These results provide some clues for future studies on the role of DSCAM overexpression in the precocious cognitive decline observed in APP transgenic mice.

唐氏综合征细胞黏附分子（Down syndrome cell adhesion molecule，DSCAM）定位于21号染色体的唐氏综合征关键区域内。DSCAM是一种广泛表达的神经发育相关蛋白，参与突触发生、神经突起生长及轴突导向过程。我们此前已证实，淀粉样前体蛋白（amyloid precursor protein，APP）转基因小鼠大脑皮层中存在DSCAM过表达现象，提示APP与DSCAM之间可能存在调控相互作用。APP转基因小鼠表现出海马依赖性学习记忆缺陷。在本预实验中，我们对16只不同月龄（1、3、6和12月龄）的APP转基因小鼠海马内DSCAM表达的年龄相关性变化进行了检测。我们采用莫里斯水迷宫（Morris water maze，MWM）对APP转基因小鼠及同月龄野生型同窝仔鼠（WTs）的海马依赖性空间记忆进行评估，并分别通过免疫组织化学、qRT-PCR以及蛋白质印迹（western blotting）检测了海马内DSCAM的细胞分布情况，以及mRNA和蛋白水平的总表达量。结果显示，APP转基因小鼠在莫里斯水迷宫实验中表现出空间记忆缺陷；在齿状回颗粒细胞层及海马锥体细胞层中可观察到强烈的DSCAM免疫反应阳性信号。在1月龄和3月龄时，APP转基因小鼠海马内DSCAM的mRNA及蛋白总表达水平显著高于野生型同窝仔鼠；两组小鼠的DSCAM表达均随月龄增长而降低，但APP转基因小鼠的表达水平仍持续高于野生型同窝仔鼠。APP转基因小鼠在出生后12个月内的海马组织中均存在DSCAM过表达现象，尤其在发育至成年阶段更为显著。综上，上述结果表明DSCAM与存在神经病理改变及行为缺陷的APP转基因小鼠之间存在相关性，本研究结果为后续探索DSCAM过表达在APP转基因小鼠所观察到的早发性认知衰退中的作用提供了一定线索。