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不断的调节。蛋白质片段如淀粉样β肽（Abeta）在脑实质和脉管系统内的积累提供了一种改变的环境，在这种环境中，稳态和修复过程必须起作用。我们项目的中心主题是特异性的，细胞相关的辅助因子，RAGE （AGEs受体）和ABAD （Abeta结合酒精脱氢酶）对于集中低水平的Abeta对脆弱细胞的影响至关重要，这与阿尔茨海默病（AD）和脑血管淀粉样血管病（CAA）的早期致病性有关。然而，在不同的情况下，这些相同的辅助因子似乎在触发神经保护通路和通过宿主反应机制的复杂整合协调修复过程中发挥关键作用。项目1通过将靶向皮质神经元和/或小胶质细胞中过表达RAGE的转基因（Tg）小鼠与过表达突变体betaAPP的小鼠杂交，评估RAGE在中枢神经系统（CNS）中增强abeta诱导的细胞应激中的作用，后者导致abeta丰富的环境。项目2研究了RAGE在周围神经系统（PNS）中的保护作用；在损伤的周围神经和浸润的巨噬细胞中，RAGE的短暂表达与另外两种RAGE配体两性素和EN-RAGEs（细胞外，新发现的RAGE结合蛋白）相互作用，这两种配体也存在于损伤部位。在PNS中，以增强已识别的RAGE结合蛋白)，这两种蛋白也存在于PNS损伤部位，以增强修复机制。项目3-4通过Tg（#3）和体外模型（#4），以及结构研究来探测ABAD-Abeta复合物（#4），将AD慢性细胞扰动的概念推断为ABAD酶，ABAD酶是Abeta在富含Abeta的环境中介导活性氧中间体和醛生成的细胞内靶标。RAGE和ABAD激活触发的重叠细胞效应机制的分析，将产生关键的共享分子工具和动物模型，并为四个项目之间的协同作用提供基础。在本项目结束时，我们期望能够获得RAGE和ABAD参与神经元扰动和修复的新的重要信息，作为评估它们作为神经退行性疾病未来治疗靶点的疗效的第一步。

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.