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连续的调制。脑实质和脉管系统内蛋白质片段如淀粉样β-肽（Abeta）的积累提供了一种改变的环境，其中稳态和修复过程必须是可操作的。我们计划项目的中心主题是，特定的细胞相关辅因子，AGEs受体（Receptor for AGEs）和ABAD（Abeta binding alcohol dehydrogenase）对于集中低水平Abeta的影响至关重要，与阿尔茨海默病（AD）和脑血管淀粉样血管病（CAA）的早期致病阶段相关，对脆弱细胞。然而，在不同的环境中，这些相同的辅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来协调修复过程中起着关键作用。项目1通过将在皮质神经元和/或小胶质细胞中靶向过表达β-APP的转基因（Tg）小鼠与过表达突变体β-APP的小鼠杂交，评估β-APP在中枢神经系统（CNS）中增强A β诱导的细胞应激中的作用，后者导致富含A β的环境。项目2研究了在外周神经系统（PNS）中的对比保护作用;在损伤的外周神经和浸润性巨噬细胞中的瞬时表达与两种其他β-受体配体，β-terin和EN-RAGE（细胞外，新鉴定的β-受体结合蛋白）相互作用，这两种蛋白也存在于损伤部位。在PNS中，以增强鉴定的结合蛋白），这两种蛋白也存在于PNS的损伤部位，以增强修复机制。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是使用Tg（#3）和体外模型（#4）在富含Abeta的环境中介导活性氧中间体和醛类产生的Abeta的细胞内靶标，以及结构研究去探测ABAD-Abeta复合物（#4）。通过激活ABAD和ABAD触发的重叠细胞效应器机制的分析，产生了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了基础。在这个研究项目的最后，我们期望产生新的和重要的信息，这些信息与神经元扰动和修复中的ABAD相关，作为评估其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.