Münch G, Kuhla B, Lüth H-J, Arendt T, Robinson S R
Neuroimmunological Cell Biology Unit, Interdisciplinary Center for Clinical Research (IZKF) Leipzig, Inselstrasse 22, 04103 Leipzig, Germany.
Biochem Soc Trans. 2003 Dec;31(Pt 6):1397-9. doi: 10.1042/bst0311397.
Accumulation of insoluble protein deposits and their cross-linking by AGEs (advanced glycation end products) in the brain is a feature of aging and neurodegeneration, especially in AD (Alzheimer's disease). In AD, two types of fibrillar protein aggregates are present: extracellular deposits (plaques) consisting mainly of Abeta (beta-amyloid peptide), and intracellular deposits (tangles) composed predominantly of microtubule-associated protein tau. Both plaques and tangles are modified by AGEs, which occurs particularly at lysine and arginine residues. Interaction of a synthetic amyloid plaque (fibrillar Abeta) with microglia leads to a strong pro-inflammatory response, indicating that priming of immune cells with beta-amyloid potentiates their response to secondary stimuli such as AGE and cytokines such as interferon-gamma. Formation of hyperphosphorylated and cross-linked microtubule-associated protein tau aggregates, especially tau dimers as the first step in tangle formation, can be induced in vitro by the combination of okadaic acid, a PP2A phosphatase inhibitor, and methylglyoxal. These results suggest that excess production of reactive carbonyl compound ("carbonyl stress") and subsequent AGE formation can contribute to cross-linking of protein fibrils and to pathological pro-inflammatory signalling, which all contribute to pathological changes and dementia progression in AD. However, the human brain has developed the glyoxalase system, a most effective defence system to scavenge small dicarbonyl compounds such as glyoxal and methylglyoxal. Very importantly, this system needs GSH as a rate-limiting cofactor. Since GSH is limited under conditions of oxidative stress and inflammation, supplementation with antioxidants such as lipoic acid, vitamin E or flavonoids could indirectly strengthen the anti-glycation defence system in AD. In addition, synthetic carbonyl scavengers and anti-inflammatory drugs could also be valuable drugs for the "anti-glycation" treatment of AD.
大脑中不溶性蛋白质沉积物的积累及其被晚期糖基化终产物（AGEs）交联是衰老和神经退行性变的一个特征，在阿尔茨海默病（AD）中尤为明显。在AD中，存在两种类型的纤维状蛋白质聚集体：主要由β-淀粉样肽（Aβ）组成的细胞外沉积物（斑块），以及主要由微管相关蛋白tau组成的细胞内沉积物（缠结）。斑块和缠结都被AGEs修饰，这种修饰尤其发生在赖氨酸和精氨酸残基处。合成淀粉样斑块（纤维状Aβ）与小胶质细胞的相互作用会引发强烈的促炎反应，这表明用β-淀粉样蛋白预处理免疫细胞会增强它们对AGEs和干扰素-γ等细胞因子等二次刺激的反应。冈田酸（一种PP2A磷酸酶抑制剂）和甲基乙二醛联合使用可在体外诱导形成高度磷酸化和交联的微管相关蛋白tau聚集体，尤其是tau二聚体作为缠结形成的第一步。这些结果表明，活性羰基化合物的过量产生（“羰基应激”）以及随后的AGEs形成可能导致蛋白质纤维的交联和病理性促炎信号传导，所有这些都促成了AD中的病理变化和痴呆进展。然而，人类大脑已经发展出乙二醛酶系统，这是一种清除乙二醛和甲基乙二醛等小双羰基化合物的最有效防御系统。非常重要的是，该系统需要谷胱甘肽（GSH）作为限速辅因子。由于在氧化应激和炎症条件下GSH有限，补充抗氧化剂如硫辛酸、维生素E或类黄酮可以间接增强AD中的抗糖基化防御系统。此外，合成羰基清除剂和抗炎药物也可能是用于AD“抗糖基化”治疗的有价值药物。
