Intraneuronal amyloid-β plays a role in mediating the synergistic pathological effects of apoE4 and environmental stimulation
Intraneuronal amyloid-β plays a role in mediating the synergistic pathological effects of apoE4 and environmental stimulation
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DOI：
10.1111/j.1471-4159.2007.04810.x
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发表时间：
2007-11-01
影响因子：
4.7
通讯作者：
Michaelson, Daniel M.
中科院分区：
文献类型：
--
作者：
Levi, Ofir;Dolev, Iftach;Michaelson, Daniel M.
载脂蛋白E4（apoE4）是阿尔茨海默病（Alzheimer's disease，AD）最常见的遗传危险因子，其等位基因E4可抑制apoE4转基因小鼠脑内的突触发生和神经发生，并刺激其凋亡。在本研究中，我们调查的假设，脑活动依赖性损伤的神经元可塑性，诱导的apoE4，介导的淀粉样蛋白级联反应。重要的是，我们发现，暴露于富含apoE4或阿尔茨海默病良性等位基因apoE3的转基因小鼠中，这些小鼠的淀粉样β肽（A β）和apoE的海马水平同样升高，但这些小鼠中A β的聚集程度和空间分布明显受apoE基因型的影响。因此，环境刺激触发了细胞外斑块样A β沉积物的形成和apoE4小鼠脑中神经元内特异性寡聚A β的积累。进一步的实验表明，海马齿状回神经元对apoE4和环境刺激特别敏感，并且这些神经元特异性地富含寡聚化A β和apoE。这些发现表明，apoE4诱导的神经可塑性损伤与神经元内A β的积累有关，并表明寡聚化A β介导了apoE4和环境刺激的协同病理效应。
The allele E4 of apolipoprotein E4 (apoE4), which is the most prevalent genetic risk factor of Alzheimer's disease (AD), inhibits synaptogenesis and neurogenesis and stimulates apoptosis in brains of apoE4 transgenic mice that have been exposed to an enriched environment. In the present study, we investigated the hypothesis that the brain activity-dependent impairments in neuronal plasticity, induced by apoE4, are mediated via the amyloid cascade. Importantly, we found that exposure of mice transgenic for either apoE4, or the Alzheimer's disease benign allele apoE3, to an enriched environment elevates similarly the hippocampal levels of amyloid-beta peptide (A beta) and apoE of these mice, but that the degree of aggregation and spatial distribution of A beta in these mice are markedly affected by the apoE genotype. Accordingly, environmental stimulation triggered the formation of extracellular plaque-like A beta deposits and the accumulation of intra-neuronal oligomerized A beta specifically in brains of apoE4 mice. Further experiments revealed that hippocampal dentate gyrus neurons are particularly susceptible to apoE4 and environmental stimulation and that these neurons are specifically enriched in both oligomerized A beta and apoE. These findings show that the impairments in neuroplasticity which are induced by apoE4 following environmental stimulation are associated with the accumulation of intraneuronal A beta and suggest that oligomerized A beta mediates the synergistic pathological effects of apoE4 and environmental stimulation.