Behl C, Holsboer F
Max-Planck-Institut für Psychiatrie, Klinisches Institut, München.
Fortschr Neurol Psychiatr. 1998 Mar;66(3):113-21. doi: 10.1055/s-2007-995246.
Alzheimer's disease (AD) is one of the most frequent causes of dementia in the aged. The elucidation of the pathomechanisms of this neurodegenerative disease with age, as the only risk factor for the majority of cases, is in the centre of the efforts of molecular and cellular neurobiology in preclinical research. Various findings point to the involvement of the amyloid beta protein (A beta) in the pathogenesis and progression of AD. Precipitated A beta aggregates are found in the brain of AD patients post mortem in the so-called plaques, a major histopathological hallmark of this progressive destructive disease. A beta can be toxic to cultivated neuronal cells only in its aggregated fibril form. After interaction with the neuronal cell membrane, these aggregates can induce intracellular oxidative events and can lead to the release of so-called free radicals. This is just one important finding for the involvement of oxidative events in the nerve cell degeneration in AD supporting the oxidative stress hypothesis. Furthermore, different neurochemical methods revealed many additional traits and scars of oxidative reactions in the brain of AD patients. Inflammatory events also seem to take part in the generation of an oxidative environment and therefore in nerve cell death as well. In addition, various age-dependent pathophysiological changes can increase neuronal vulnerability. Different antioxidants can protect cultivated neurons against A beta toxicity, but also against other oxidative stressors relevant to the disease. Besides the classical lipophilic antioxidant vitamin E, the female sex hormone oestrogen could also play an important neuroprotective role as an antioxidant, as was shown recently. Oestrogen, oestrogen derivatives, but also other potential free radical scavengers could block the accumulation of oxidative events on the long run and could, therefore, possibly slow down or prevent progressive nerve cell death of AD, which occurs over decades. If future clinical trials using antioxidants as neuroprotectants in AD would also support the oxidative stress hypothesis of the aetiopathogenesis of AD, antioxidants identified in the laboratory could then find their way more and more into the clinical treatment of Alzheimer's dementia.
阿尔茨海默病（AD）是老年人痴呆最常见的病因之一。阐明这种神经退行性疾病的发病机制，鉴于年龄是大多数病例的唯一风险因素，处于临床前研究中分子和细胞神经生物学努力的核心。各种研究结果表明β淀粉样蛋白（Aβ）参与了AD的发病机制和进展。死后在AD患者大脑中发现沉淀的Aβ聚集体，存在于所谓的斑块中，这是这种进行性破坏性疾病的一个主要组织病理学标志。Aβ只有以聚集的纤维形式才对培养的神经元细胞有毒性。与神经元细胞膜相互作用后，这些聚集体可诱导细胞内氧化事件，并可导致所谓自由基的释放。这只是支持氧化应激假说的关于氧化事件参与AD神经细胞变性的一个重要发现。此外，不同的神经化学方法揭示了AD患者大脑中氧化反应的许多其他特征和痕迹。炎症事件似乎也参与了氧化环境的产生，因此也参与了神经细胞死亡。此外，各种年龄相关的病理生理变化会增加神经元的易损性。不同的抗氧化剂可以保护培养的神经元免受Aβ毒性，也可以抵抗与该疾病相关的其他氧化应激源。除了经典的亲脂性抗氧化剂维生素E外，女性性激素雌激素最近也显示出作为抗氧化剂可能发挥重要的神经保护作用。雌激素、雌激素衍生物以及其他潜在的自由基清除剂从长远来看可以阻止氧化事件的积累，因此可能减缓或预防AD中数十年发生的进行性神经细胞死亡。如果未来使用抗氧化剂作为AD神经保护剂的临床试验也支持AD病因发病机制的氧化应激假说，那么实验室中鉴定出的抗氧化剂可能会越来越多地应用于阿尔茨海默病痴呆的临床治疗。
