NEUROFIBRILLARY PATHOLOGY IN ALZHEIMER DISEASE

描述：（改编自申请人的摘要）：我们的研究 实验室已经确定了氧化应激和氧化蛋白 阿尔茨海默病（Alzheimer disease，AD）的主要病理改变之一是蛋白质修饰。 这些研究是在2004年资助期内实现各项目标的直接成果。 我们确定神经元缠结（NFT）与 交联的蛋白质在老年人中的溶解度特性 晚期糖基化终产物（AGE） 然后，我们证明了抗体， AGE识别NFT和老年斑（senile plaques，SP）。 当年龄改变时， 引入神经母细胞瘤细胞，脂质过氧化作用增加， 通过血红素加氧酶-1（HO-1）和NF-κ B强氧化应激反应， 知道了 HO-1免疫反应性在含NFT的神经元中也增加， 但在对照组的大脑中却没有。 蛋白质的直接氧化是 也发现在NFT以及神经元细胞质和神经胶质细胞核中， AD病例的神经元，而不是年龄匹配的对照脑，表明氧化 损伤并不局限于病变，氧化应激可能 在NFT和SP形成之前。对此的进一步建议来自于 针对NFT产生的单克隆抗体，其识别 神经丝蛋白以及t.后者，Alz 50，它承认一个 可还原的（即，早期）t的糖化修饰，是最早的标志物 AD的细胞骨架改变。 我们现在建议确定AGE修改的三个特征， 对于了解它们在AD发病机制中的作用至关重要。 第一、 确定哪些蛋白质被修饰，以及它们何时被修饰， 损伤形成。 第二，评估AGE修饰NFT的效果， SP对抗蛋白水解和吞噬作用的影响。 第三，评估 各种脑细胞类型对AGE修饰的氧化应激反应 proteins. 这些研究将探讨AGE修饰是否是一种特异性的 和神经细胞骨架的早期修饰，其在损伤中的作用 细胞对AGE的持续性和差异反应。

DESCRIPTION: (Adapted from Applicant's Abstract): Studies from our laboratory have established that oxidative stress and oxidative protein modification are salient features of the lesions of Alzheimer disease (AD). These studies are a direct outcome of the aims of the funding period in which we determined that neurofibrillary tangles (NFT) share the same solubility properties of proteins in aged individuals, which are crosslinked by advanced glycation endproducts (AGE). We then demonstrated antibodies to AGE recognize NFT and senile plaques (SP). When AGE modified-t was introduced to neuroblastoma cells, lipid peroxidation was increased and a strong oxidative stress response by heme oxygenase-1 (HO-1) and NFkb was noted. HO-1 immunoreactivity is also increased in NFT-containing neurons, but is absent in brains of control cases. Direct oxidation of protein was also found in NFT as well as neuronal cytoplasm and nuclei of glia and neurons of AD cases but not age matched control brains indicating oxidative damage is not restricted to the lesions and that oxidative stress likely precedes the formation of NFT and SP. Further suggestions of this come from monoclonal antibodies raised to NFT which recognize AGE adducts of neurofilament proteins as well as t. The latter, Alz50, which recognizes a reducible (i.e., early) glycation modification of t, is the earliest marker of cytoskeletal alteration of AD. We now propose to determine three features of the AGE modification that will be essential to understanding their role in AD pathogenesis. First, determine which proteins are modified and when they become modified during lesion formation. Second, assess the effect of AGE modification of NFT and SP on resistance to proteolysis and phagocytosis. Third, evaluate the oxidative stress response of various brain cell types to AGE modified proteins. These studies will address whether AGE modification is a specific and early modification of the neuronal cytoskeleton, its role in lesion persistence and the differential response of cells to AGE.