Wong A, Lüth H J, Deuther-Conrad W, Dukic-Stefanovic S, Gasic-Milenkovic J, Arendt T, Münch G
Neuroimmunological Cell Biology, IZKF Leipzig, Johannisallee 30a, 04103, Leipzig, Germany.
Brain Res. 2001 Nov 30;920(1-2):32-40. doi: 10.1016/s0006-8993(01)02872-4.
Advanced glycation endproducts (AGEs), protein-bound oxidation products of sugars, have been shown to be involved in the pathophysiological processes of Alzheimer's disease (AD). AGEs induce the expression of various pro-inflammatory cytokines and the inducible nitric oxide synthase (iNOS) leading to a state of oxidative stress. AGE modification and resulting crosslinking of protein deposits such as amyloid plaques may contribute to the oxidative stress occurring in AD. The aim of this study was to immunohistochemically compare the localization of AGEs and beta-amyloid (Abeta) with iNOS in the temporal cortex (Area 22) of normal and AD brains. In aged normal individuals as well as early stage AD brains (i.e. no pathological findings in isocortical areas), a few astrocytes showed co-localization of AGE and iNOS in the upper neuronal layers, compared with no astrocytes detected in young controls. In late AD brains, there was a much denser accumulation of astrocytes co-localized with AGE and iNOS in the deeper and particularly upper neuronal layers. Also, numerous neurons with diffuse AGE but not iNOS reactivity and some AGE and iNOS-positive microglia were demonstrated, compared with only a few AGE-reactive neurons and no microglia in controls. Finally, astrocytes co-localized with AGE and iNOS as well as AGE and were found surrounding mature but not diffuse amyloid plaques in the AD brain. Our results show that AGE-positive astrocytes and microglia in the AD brain express iNOS and support the evidence of an AGE-induced oxidative stress occurring in the vicinity of the characteristic lesions of AD. Hence activation of microglia and astrocytes by AGEs with subsequent oxidative stress and cytokine release may be an important progression factor in AD.
晚期糖基化终末产物（AGEs）是糖与蛋白质结合的氧化产物，已被证明与阿尔茨海默病（AD）的病理生理过程有关。AGEs诱导多种促炎细胞因子和诱导型一氧化氮合酶（iNOS）的表达，导致氧化应激状态。AGE修饰以及由此导致的蛋白质沉积物（如淀粉样斑块）交联可能促成AD中发生的氧化应激。本研究的目的是通过免疫组织化学方法比较正常和AD大脑颞叶皮质（22区）中AGEs、β-淀粉样蛋白（Aβ）与iNOS的定位。在老年正常个体以及早期AD大脑（即等皮质区域无病理发现）中，与年轻对照组未检测到星形胶质细胞相比，少数星形胶质细胞在神经元上层显示出AGE和iNOS的共定位。在晚期AD大脑中，在更深层尤其是神经元上层有更多与AGE和iNOS共定位的星形胶质细胞密集聚集。此外，与对照组中仅有少数AGE反应性神经元且无微神经胶质细胞相比，发现了许多具有弥漫性AGE反应但无iNOS反应性的神经元以及一些AGE和iNOS阳性的小胶质细胞。最后，在AD大脑中发现与AGE和iNOS以及AGE共定位的星形胶质细胞围绕着成熟而非弥漫性的淀粉样斑块。我们的结果表明，AD大脑中AGE阳性的星形胶质细胞和小胶质细胞表达iNOS，并支持在AD特征性病变附近发生AGE诱导的氧化应激的证据。因此，AGEs激活小胶质细胞和星形胶质细胞，随后产生氧化应激和细胞因子释放，可能是AD中的一个重要进展因素。
