Reelin signaling antagonizes β-amyloid at the synapse
Reelin signaling antagonizes β-amyloid at the synapse
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DOI：
10.1073/pnas.0908176106
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发表时间：
2009-09-15
影响因子：
11.1
通讯作者：
Herz, Joachim
中科院分区：
文献类型：
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作者：
Durakoglugil, Murat S.;Chen, Ying;Herz, Joachim
淀粉样前体蛋白（APP）的异常加工和β-淀粉样蛋白（A β）斑块积聚是阿尔茨海默病（AD）的定义特征，AD是一种遗传复杂的神经退行性疾病，其特征在于进行性突触丢失和神经元细胞死亡。A β通过改变AMPA和NMDA受体的内吞作用和运输，部分诱导突触功能障碍。Reelin是一种神经调质，其通过突触后ApoE受体Apoer 2和Vldlr的信号传导增加突触能神经传递，从而有效地增强突触可塑性。在这里，我们表明，Reelin可以防止长时程增强和NMDA受体的抑制，这是由A β水平诱导的，与AD患者大脑中存在的水平相当。这种逆转依赖于Src家族酪氨酸激酶的激活。在高浓度的A β肽下，Reelin不再能克服A β诱导的功能抑制，这与Reelin依赖的NR 2亚基磷酸化的完全阻断一致。我们提出了一个模型，其中A β，Reelin和ApoE受体调节神经传递，从而作为突触增益控制的相对调节器的突触稳定性。
Abnormal processing of the amyloid precursor protein (APP) and beta-amyloid (A beta) plaque accumulation are defining features of Alzheimer disease (AD), a genetically complex neurodegenerative disease that is characterized by progressive synapse loss and neuronal cell death. A beta induces synaptic dysfunction in part by altering the endocytosis and trafficking of AMPA and NMDA receptors. Reelin is a neuromodulator that increases glutamatergic neurotransmission by signaling through the postsynaptic ApoE receptors Apoer2 and Vldlr and thereby potently enhances synaptic plasticity. Here we show that Reelin can prevent the suppression of long-term potentiation and NMDA receptors, which is induced by levels of A beta comparable to those present in an AD-afflicted brain. This reversal is dependent upon the activation of Src family tyrosine kinases. At high concentrations of A beta peptides, Reelin can no longer overcome the A beta induced functional suppression and this coincides with a complete blockade of the Reelin-dependent phosphorylation of NR2 subunits. We propose a model in which A beta, Reelin, and ApoE receptors modulate neurotransmission and thus synaptic stability as opposing regulators of synaptic gain control.