PS1 regulates processing and signaling of ephrinB/EphB

谷氨酸诱导的兴奋性毒性和氧化应激是其发病机制之一。 阿尔茨海默病(AD)。我们发现，eparinB配体保护原代培养的神经元免受 谷氨酸和氧化应激诱导的毒性，以及肾上腺素Bls的神经保护活性依赖于 在EphB受体(EphBRs)和早老素(PS1)上，参与家族性AD(FAD)的蛋白质。我们也 观察PS1介导脑源性神经营养因子(BDNF)的神经保护作用。 有趣的是，bls和bdnf的神经保护作用依赖于PS1的两个等位基因，因为 缺乏一个或两个等位基因会导致营养因子诱导的神经保护受到抑制。 此外，脑源性神经营养因子和脑源性神经营养因子的神经保护活性也显著降低。 PS1的Fad突变体为杂合子或纯合子。相比之下，神经保护功能 碱性成纤维细胞生长因子既不受WT的影响，也不受突变体PSL的影响。我们的数据表明，一种新的 FAD神经退变机制中表达PS1突变体的脑神经元可能有 对神经保护因素的反应能力降低，因此更容易受到有毒侮辱 野生型神经元。这种神经保护的减弱可能会导致神经元损失率增加甚至超过 多年来，在严重的神经元种群枯竭中。 在此，我们建议进一步研究PS1及其FAD突变体对神经保护的作用。 用原代神经元培养和用PS1基因敲除和FAD方法研究营养因子的体外功能 敲进去的老鼠模型。我们将使用与PS1相同的技术来探索 早老素2(PS2)和淀粉样前体蛋白(APP)的神经保护作用此外，我们还将 探索PS1神经保护功能的机制，包括MP/y-分泌酶的作用 受体加工和内吞作用在PS1、BDNF和ewitinBls神经保护活性中的作用 PS1和FAD突变体对配体诱导的受体磷酸化和下游信号的影响。 相关性(请参阅说明)： 兴奋性毒性和氧化应激与神经退行性变和阿尔茨海默病(AD)有关。我们 发现PSL，一种与家族性AD有关的蛋白质，介导了脑因子的神经保护功能，如 和脑源性神经营养因子。在没有PS1的情况下，这些因素无法保护神经元。有趣的是，基因 促进AD的变化干扰了PS1的神经保护功能。我们的发现具有重要意义 对于神经退行性变和MAV机制的研究为AD的治疗干预提供了新的靶点。

Glutamate-induced excitotoxicity and oxidative stress are mechanisms implicated in the pathogenesis of Alzheimer's disease (AD). We found that ephrinB ligands (ephrinBLs) protect primary neuronal cultures from glutamate- and oxidative stress-induced toxicity and that the neuroprotective activities of ephrinBLs depend on EphB receptors (EphBRs) and presenilini (PS1), a protein involved in familial AD (FAD). We also observed that PS1 mediates the neuroprotective effects of brain-derived neurotrophic factor (BDNF). Interestingly, the neuroprotective activities of ephrinBLs and BDNF depend on both alleles of PS1 because absence of either one or both alleles results in the inhibition of trophic factor-induced neuroprotection. Furthermore, the neuroptotective activities of ephrinBLs and BDNF are significantly reduced in neurons either heterozygous or homozygous for FAD mutants of PS1. In contrast, the neuroprotective function of basic fibroblast growth factor (bFGF) is affected neither by WT nor by mutant PSl Our data suggest a novel mechanism of neurodegeneration in FAD where brain neurons expressing FAD mutants of PS1 may have reduced ability to respond to neuroprotective factors and therefore are more vulnerable to toxic insults then wild type neurons. This decreased neuroprotection may result in increased rates of neuronal loss and over many years, in severe depletion of neuronal populations. Here we propose tp investigate further the effects of PS1 and its FAD mutants oh the neuroprotective function of trophic factors in vitro using primary neuronal cultures and in vivo using PS1 knockout and FAD knock-in mouse models. We will use the same technology we employed for PS1 to explore the neuroprotective activities of presenilin 2 (PS2) and the amyloid precursor protein (APP). In addition, we will explore mechanisms involved in the neuroprotective function of PS1 including the role of MP/y-secretase receptor processing and endocytosis in the neuroprotecive activities of PS1, BDNF and ephrinBLs and the effects of PS1 and FAD mutants on ligand-induced receptor phosphorylation and downstream signaling. RELEVANCE (See instructions): Excitotoxicity and oxidative stress are implicated in neurodegeneration and Alzheimer disease (AD). We found that PSl, a protein involved in familial AD, mediates the neuroprotective functions of brain factors like ephrinB and BDNF. These factors are unable to protect neurons in the absence of PS1. Interestingly, genetic changes that promote AD interfere with the neuroprotective function of PS1. Our findings have implications for the mechanism of neurodegeneration and mav provide novel targets for therapeutic intervention in AD.