CELLULAR COFACTORS, NEURONAL STRESS & RESCUE, AGING & AD

在衰老过程中，神经元对内源性和外源性环境应激的反应经历了持续的调制。蛋白质片段，如淀粉样β-肽(Abeta)，在脑实质和血管系统中的积累提供了一种修改的环境，在这种环境中，内环境平衡和修复过程必须是有效的。我们计划项目的中心主题是，特定的细胞相关辅助因子RAGE(AGEs受体)和ABAD(Abeta结合酒精脱氢酶)对于将与阿尔茨海默病(AD)和脑血管淀粉样血管病变(CAA)的早期致病阶段相关的低水平Abeta的影响集中在脆弱细胞上至关重要。然而，在不同的环境中，这些相同的辅助因子似乎在触发神经保护途径和通过复杂的宿主反应机制整合来协调修复过程中发挥着关键作用。项目1评估了RAGE在中枢神经系统(CNS)中的作用，通过将皮质神经元和/或小胶质细胞中RAGE靶向过表达的转基因(TG)小鼠与过度表达突变体BetaAPP的小鼠杂交，后者导致了Aβ丰富的环境，评估了RAGE在增强Aβ诱导的细胞应激中的作用。项目2研究了RAGE在周围神经系统(PNS)中的保护作用的对比；RAGE在受损的周围神经和浸润性巨噬细胞中的瞬时表达与另外两种RAGE配体--两性蛋白和新近发现的RAGE结合蛋白--相互作用，这两种配体也存在于损伤部位。在三叉神经节中，增强已识别的RAGE结合蛋白)，这两种蛋白也存在于三叉神经节的损伤部位，以加强修复机制。项目3-4将我们在AD中的慢性细胞扰动的概念外推到酶ABAD，ABAD是Abeta的一个细胞内靶标，使用TG(#3)和体外模型(#4)在Abeta丰富的环境中介导活性氧中间体和醛的产生，以及结构研究去探索ABAD-Abeta复合体(#4)。对RAGE和ABAD激活触发的重叠细胞效应机制的分析在关键的共享分子工具和动物模型中取得了结果，并为四个项目之间的协同提供了基础。在该计划项目结束时，我们预计将产生与RAGE和ABAD参与神经元干扰和修复相关的新的重要信息，作为评估它们作为未来神经退行性疾病治疗靶点的有效性的第一步。

During aging, the neuronal response to endogenous and exogenous environmental stress undergoes continuous modulation. The accumulation of protein fragments, such as amyloid beta-peptide (Abeta), within brain parenchyma and vasculature provides a modified context in which homeostatic and reparative processes must be operative. The central theme of our Program Project is that specific, cell-associated cofactors, RAGE (Receptor for AGEs) and ABAD (Abeta binding alcohol dehydrogenase) are critical for concentrating the effects of low levels of Abeta, relevant to early stages of pathogenicity in Alzheimer's disease (AD) and cerebrovascular amyloid angiopathy (CAA), on vulnerable cells. Yet, in distinct settings, these same cofactors appear to have a pivotal role in triggering neuroprotective pathways and in orchestrating reparative processes through a complex integration of host response mechanisms. Project 1 evaluates the role of RAGE in the central nervous system, (CNS) in the potentiation of Abeta-induced cell stress by cross-breeding transgenic (Tg) mice with targeted over-expression of RAGE in cortical neurons and/or microglia with mice over-expressing mutant betaAPP, the latter resulting in an Abeta-rich environment. Project 2 examines a contrasting a protective role of RAGE in the peripheral nervous system (PNS); transient expression of RAGE in injured peripheral nerve and infiltrating macrophages interacts with two other RAGE ligands, amphoterin and EN-RAGEs (Extracellular, Newly- identified RAGE binding proteins), both of which are also present at sites of injury. in the PNS, to enhance identified RAGE binding proteins), both of which are also present at sites of injury in the PNS, to enhance reparative mechanisms. Projects 3-4 extrapolate our concept of chronic cellular perturbation in AD to the enzyme ABAD, an intracellular target of Abeta mediating generation of reactive oxygen intermediates and aldehydes in an Abeta-rich environment using Tg (#3) and in vitro models (#4), as well as structural studies go to probe ABAD-Abeta complex (#4). Analysis of overlapping cellular effector mechanisms triggered by activation of RAGE and ABAD results in critical shared molecular tools and animals models, and provides the basis for synergy among the four projects. At the end of this PROGRAM PROJECT, we expect to have generated new and important information related to the involvement of RAGE and ABAD in neuronal perturbation and repair as a first step in evaluating their efficacy as future therapeutic targets in neurodegenerative disorders.