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Ephrin B2 receptor signaling in Alzheimer diseased brain - a safeguard against neurodegeneration?

阿尔茨海默病大脑中的 Ephrin B2 受体信号传导 - 预防神经退行性变的保障？

基本信息

批准号：
279728577
负责人：
Privatdozent Dr. Arne Herring
金额：
--
依托单位：
Institut für Neuropathologie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2015
资助国家：
德国
起止时间：
2014-12-31 至 2019-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/279728577?language=en
关键词：
Ephrin B2 receptor signaling Alzheimer

项目摘要

Ephrin B2 receptor (EPHB2) signaling, conducted by binding of Ephrin ligand EFNB2 to EPHB2, contributes to phenotypical brain plasticity at various levels. It coordinates angiogenesis and autophagy as well as memory and learning related axonal guidance / dendritic arborization and synapto/neurogenesis. Further, anxiety is controlled by kallikrein 8 (KLK8) mediated EPHB2 proteolysis and subsequent increased expression of FK506 binding protein 5 (FKBP5) which in turn regulates glucocorticoid receptor (GR) sensitivity in the amygdala. All the above named behavioral and structural processes that are controlled by EPHB2 are also disturbed / impaired in the Alzheimer disease (AD) affected brain. Therefore, it is very suggestive that EPHB2 signaling might be also involved in the pathogenesis of AD. The overall objective of this proposal is to elucidate the impact of EPHB2 signaling on the pathogenesis of AD. In particular, we aim to verify whether reversing EPHB2 depletion by inhibiting its proteolytic enzyme KLK8 would mitigate AD pathology, and if so to unravel the underlying mechanisms of this effect. First, in a descriptive approach, we aim to assess the regional and temporal specific mRNA and protein expression pattern of EPHB2 signaling members (EPHB2, EFNB2, KLK8, FKBP5, GR) in AD-vulnerable human and murine brain during the course of the disease (and physiological aging). Second, using an in vitro approach, we will mechanistically analyze the effect of pharmacological manipulation of EPHB2 signaling by a KLK8-inhibiting antibody (that protects EPHB2 from degradation) on Abeta pathology, autophagy and cell survival in primary neuronal and glial cell cultures derived from Tg mice. In a reciprocal approach, by using activated synthetic KLK8 we will then reduce EPHB2 levels and verify the above results inversely. Third, by using an in vivo approach, we will study the functional consequence of reversing EPHB2 signaling disturbance through intraventricular anti-KLK8 antibody administration to Tg mice (and to Wt mice serving as physiological baseline) on anxiety behavior as well as on learning and memory performances. Furthermore, the effect of this pharmacological manipulation on amygdalar molecules involved in anxiety generation and on hippocampal and cortical structural neuro-plasticity will be studied. Moreover, by performing molecular, structural and ultra-structural analyzes the impact of EPHB2 protection on APP and Abeta metabolism, Abeta clearance, the neurovascular unit and on autophagy machinery will be examined. Results from this project may open up new avenues in the treatment of AD.

肾上腺素B2受体(EPHB2)信号通过与EPHB2结合，在不同水平上参与脑的表型可塑性。它协调血管生成和自噬，以及记忆和学习相关的轴突引导/树突树枝形成和突触/神经发生。此外，焦虑是由激肽释放酶8(KLK8)介导的EPHB2蛋白分解和随后FK506结合蛋白5(FKBP5)的表达增加控制的，FKBP5反过来调节杏仁核中糖皮质激素受体(GR)的敏感性。所有上述由EPHB2控制的行为和结构过程在阿尔茨海默病(AD)影响的大脑中也受到干扰/损害。因此，EPHB2信号通路可能也参与了AD的发病过程。这项建议的总体目标是阐明EPHB2信号在AD发病机制中的作用。特别是，我们的目标是验证通过抑制EPHB2的蛋白水解酶KLK8来逆转EPHB2的耗竭是否可以减轻AD的病理，如果是这样的话，我们将揭示这种效应的潜在机制。首先，采用描述性方法，我们旨在评估EPHB2信号成员(EPHB2、EFNB2、KLK8、FKBP5、GR)在AD易感人群和小鼠脑中的区域和时间特异性mRNA和蛋白在疾病过程中(以及生理衰老)的表达模式。其次，使用体外方法，我们将从机制上分析KLK8抑制抗体(保护EPHB2免于降解)对EPHB2信号的药理操纵对来自TG小鼠的原代神经元和神经胶质细胞培养的Abeta病理、自噬和细胞存活的影响。在一种互惠的方法中，通过使用激活的合成KLK8，我们将降低EPHB2水平，并反向验证上述结果。第三，通过体内实验，我们将研究通过脑室注射抗KLK8抗体逆转EPHB2信号紊乱对焦虑行为和学习记忆成绩的影响。此外，这种药物操作对杏仁核分子参与焦虑产生的影响，以及对海马区和皮质结构神经可塑性的影响将被研究。此外，通过进行分子、结构和超结构分析，EPHB2保护对APP和Abeta代谢、Abeta清除、神经血管单位和自噬机制的影响将被检测。该项目的结果可能为AD的治疗开辟新的途径。