Reelin protects against amyloid β toxicity in vivo.
Reelin protects against amyloid β toxicity in vivo.
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DOI：
10.1126/scisignal.aaa6674
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发表时间：
2015-07-07
影响因子：
7.3
通讯作者：
Herz J
中科院分区：
文献类型：
--
作者：
Lane-Donovan C;Philips GT;Wasser CR;Durakoglugil MS;Masiulis I;Upadhaya A;Pohlkamp T;Coskun C;Kotti T;Steller L;Hammer RE;Frotscher M;Bock HH;Herz J
阿尔茨海默病（AD）是一种目前无法治愈的神经退行性疾病，也是65岁以上人群中最常见的痴呆症。AD的主要遗传危险因素是编码载脂蛋白E （ApoE4）的ε4等位基因。分泌的糖蛋白Reelin是多功能载脂蛋白E受体载脂蛋白E受体2 （Apoer2）和极低密度脂蛋白受体（Vldlr）的生理配体，可增强突触可塑性。我们之前已经证明，ApoE4的存在通过损害受体的再循环使神经元对Reelin无反应，从而降低其对β淀粉样蛋白（Aβ）寡聚物诱导的突触毒性的保护作用。在这里，我们表明当Reelin在成年小鼠中被敲除时，这些小鼠表现正常，没有明显的学习或记忆缺陷。然而，他们对淀粉样蛋白诱导的突触抑制非常敏感，并且在极少量淀粉样蛋白沉积时具有深刻的记忆和学习障碍。我们的研究结果强调了Reelin在保护大脑免受a β诱导的突触功能障碍和记忆障碍方面的生理重要性。
Alzheimer's disease (AD) is a currently incurable neurodegenerative disorder and the most common form of dementia in people over the age of 65. The predominant genetic risk factor for AD is the ε4 allele encoding apolipoprotein E (ApoE4). The secreted glycoprotein Reelin, which is a physiological ligand for the multifunctional ApoE receptors Apolipoprotein E receptor 2 (Apoer2) and very low-density lipoprotein receptor (Vldlr), enhances synaptic plasticity. We have previously shown that the presence of ApoE4 renders neurons unresponsive to Reelin by impairing the recycling of the receptors, thereby decreasing its protective effects against amyloid β (Aβ) oligomer-induced synaptic toxicity in vitro. Here, we show that when Reelin was knocked out in adult mice, these mice behaved normally without overt learning or memory deficits. However, they were strikingly sensitive to amyloid-induced synaptic suppression, and had profound memory and learning disabilities at very low amounts of amyloid deposition. Our findings highlight the physiological importance of Reelin in protecting the brain against Aβ-induced synaptic dysfunction and memory impairment.