IMMUNOCYTOCHEMICAL STUDIES ON OXIDATIVE DAMAGE IN THE BRAINS OF ALZHEIMER'S DISEASE

越来越多的证据表明，氧化应激与大脑的衰老过程以及阿尔茨海默病(AD)和唐氏综合症(DS)有关。我们用原位方法检测了家族性AD(n=12，年龄47-81岁)、散发性AD(n=22，57-93岁)、DS(n=22，0.3-y)和非痴呆患者(n=40，0.3-86岁)大脑皮层中的氧化核苷-8-羟基鸟苷(8OHG；1F7抗体)。80HG免疫反应的相对强度测量(Q500IW-EX，Leica)显示，非痴呆患者神经元80HG的表达随年龄的增长而增加。与年龄匹配的对照组相比，散发性AD和DS组的神经元80HG显著增加，而家族性AD组则不明显。有趣的是，在DS中，显著的80HG升高在时间上先于淀粉样蛋白β沉积的显著增加，而在散发性AD和DS中，8OHG水平与淀粉样蛋白β负荷率呈负相关。神经元核酸氧化是一个与年龄相关的事件，也是散发性AD和DS病理级联中的上游事件。Aβ的沉积可能与AD和DS患者对持续氧化应激的代偿反应有关。

Increasing evidence implicates oxidative stress in the aging process of the brain as well as in Alzheimer's disease (AD) and Down's syndrome (DS). We used an in situ approach to identify the oxidized nucleoside, 8-hydroxyguanosine (8OHG; the 1F7 antibody) in the cerebral cortex of familial AD with presenflin-1 mutations (n=12, age 47-81 y), sporadic AD (n = 22, 57-93 y), DS (n=22, 0.3-64 y), and non-demented patients (n=40, 0.3-86 y). Relative intensity measurements of 80HG immunoreactivity (Q500IW-EX, Leica) showed there was an age-related increase of neuronal 8OHG in non-demented patients. In sporadic AD and DS, but not in familial AD, neuronal 8OHG significantly increased compared to age-matched controls. Interestingly, significant 8OHG elevation temporally precedes the significant increase of amyloid β deposition in DS, and the levels of 8OHG inversely correlated with % amyloid β burden in sporadic AD and DS. Neuronal nucleic acid oxidation is an age-related event as well as an upstream event in the pathological cascade of sporadic AD and DS. Deposition of Aβmay be related to a compensatory response to sustained oxidative stress in AD and DS.