PS1 mediates the neuroprotective functions of the ephrinB/EphB system

兴奋性毒性，谷氨酸过度激活引起的一种神经元损伤形式 受体和氧化应激是神经损伤的机制，参与了 阿尔茨海默病(AD)的发病机制。我们发现E受体B家族的配体 蛋白质保护原代培养的神经元免受谷氨酸和氧化应激的影响- 诱导死亡。肾上腺素B配体的神经保护活性为 由它们的受体(EphB受体，EphBRs)介导，并依赖于蛋白质PS1 参与家族性阿尔茨海默病(FAD)。有趣的是，肾上腺素B的神经保护作用 取决于两个PS1等位基因，因为缺少一个等位基因(单倍体不足)会导致 严重降低了肾上腺素B的神经保护作用。此外，我们还获得了初步的 数据表明，PS1的FAD突变体干扰了eaffin B依赖的神经保护和 这种分泌酶活性可能参与了神经保护功能。 EphBR系统。 在这里，我们建议进一步研究PS1 FAD突变体和-分泌酶对 肾上腺素Bls的神经保护作用及其分子机制的研究 哪个PS1调节这一功能。我们将探讨PS1是否调节了 对EphBRs的易福林BLS及EphB和EphB的磷酸化 NMDA受体。为此，我们将使用我们的大脑皮质原代神经元培养 PS1基因敲除和FAD突变敲入转基因小鼠克隆及EphBR 我们实验室里有敲除菌落。我们还将使用我们的鼠标模型来 检测EphriBL/EphBR系统的体内神经保护功能并询问 PS1 FAD突变是否会影响这一功能。最后，我们会问PS2，一个 PS1的同源物也参与了FAD，也可能参与了ewitinB 神经保护。

Excitotoxicity, a form of neuronal damage due to excessive activation of glutamate receptors and oxidative stress are mechanisms of neuronal injury implicated in the pathogenesis of Alzheimer's disease (AD). We found that the ephrinB family of ligand proteins protects primary neuronal cultures from both glutamate- and oxidative stress- induced death. The neuroprotective activities of ephrinB ligands (ephrinBLs) are mediated by their receptors (EphB receptors, EphBRs) and depend on PS1, a protein involved in familial AD (FAD). Interestingly, the neuroprotective effect of ephrinB depends on both PS1 alleles because absence of one allele (haploinsufficiency) results in severe reduction of the ephrinB neuroprotection. Furthermore, we obtained preliminary data that FAD mutants of PS1 interfere with the ephrinB-dependent neuroprotection and that -secretase activity may be involved in the neuroprotective functions of the ephrinBL/EphBR system. Here we propose to further investigate the effects of PS1 FAD mutants and -secretase on the neuroprotective function of ephrinBLs and to elucidate molecular mechanisms by which PS1 mediates this function. We will explore whether PS1 regulates the binding of ephrinBLs to EphBRs and the ephrinBL-induced phosphorylation of both EphB and NMDA receptors. To this end we will use cortical primary neuronal cultures from our PS1 knockout and FAD mutant knock-in transgenic mouse colonies as well as EphBR knock-out colonies available in our laboratory. We will also use our mouse models to examine the neuroprotective function of the ephriBL/EphBR system in vivo and to ask whether PS1 FAD mutations affect this function. Finally, we will ask whether PS2, a homologue of PS1 also involved in FAD, may also be involved in the ephrinB neuroprotection.