Department Isquèmia Cerebral i Neurodegeneració, Institut d'Investigacions Biomèdiques de Barcelona (IIBB), CSIC-IDIBAPS, Barcelona, Spain.
J Alzheimers Dis. 2010;20(1):229-45. doi: 10.3233/JAD-2010-1365.
Alzheimer's disease (AD) is a devastating age-related neurodegenerative disease. Age is the main risk factor for sporadic AD, which is the most prevalent type. Amyloid-beta peptide (Abeta) neurotoxicity is the proposed first step in a cascade of deleterious events leading to AD pathology and dementia. Glial cells play an important role in these changes. Astrocytes provide vital support to neurons and modulate functional synapses. Therefore, the toxic effects of Abeta on astrocytes might promote neurodegenerative changes that lead to AD. Aging reduces astrocyte antioxidant defenses and induces oxidative stress. We studied the effects of Abeta(42) on cultures of human astrocytes in the presence or absence of the following pro-oxidant agents: buthionine sulfoximine (BSO), a glutathione synthesis inhibitor, and FeSO(4), which liberates redox active iron. Pro-oxidant conditions potentiated Abeta toxicity, as shown by the generation of free radicals, inflammatory changes, and apoptosis. Similar treatments were assessed in rats in vivo. A combination of Abeta(40) and Abeta(42) or Abeta(42) alone was infused intracerebroventricularly for 4 weeks. Other animal groups were also infused with BSO and FeSO(4). A long-term analysis that ended 4 months later showed greater cognitive impairment in the Morris water maze task, which was induced by Abeta plus pro-oxidant agent treatments. Pro-oxidant agents also potentiated brain tissue pathology. This was demonstrated in histological studies that showed highly increased astrocyte reactivity in AD-vulnerable areas, Abeta deposits, and oxidative damage of AD-sensitive hippocampal neurons. To increase our understanding of AD, experimental models should be used that mimic age-related brain changes, in which age-related oxidative stress potentiates the effects of Abeta.
阿尔茨海默病（AD）是一种破坏性的与年龄相关的神经退行性疾病。年龄是散发性 AD 的主要危险因素，而散发性 AD 是最常见的类型。淀粉样β肽（Abeta）神经毒性被认为是导致 AD 病理和痴呆的一系列有害事件的第一步。神经胶质细胞在这些变化中起着重要作用。星形胶质细胞为神经元提供重要的支持，并调节功能性突触。因此，Abeta 对星形胶质细胞的毒性作用可能促进导致 AD 的神经退行性变化。衰老会降低星形胶质细胞的抗氧化防御能力并诱导氧化应激。我们研究了 Abeta(42)在存在或不存在以下促氧化剂的情况下对人星形胶质细胞培养物的影响：丁硫氨酸亚砜胺（BSO），一种谷胱甘肽合成抑制剂，以及 FeSO(4)，它释放出具有氧化还原活性的铁。促氧化剂条件增强了 Abeta 的毒性，表现为自由基的产生、炎症变化和细胞凋亡。在体内对大鼠进行了类似的处理。Abeta(40)和 Abeta(42)或 Abeta(42)单独组合通过脑室内输注 4 周。其他动物组也接受了 BSO 和 FeSO(4)的输注。4 个月后结束的长期分析显示，在 Morris 水迷宫任务中认知障碍更严重，这是由 Abeta 加促氧化剂处理诱导的。促氧化剂还增强了脑组织病理学。在组织学研究中证明了这一点，这些研究显示在 AD 易损区域、Abeta 沉积和 AD 敏感海马神经元的氧化损伤中，星形胶质细胞反应性高度增加。为了增加对 AD 的理解，应使用模拟与年龄相关的大脑变化的实验模型，其中与年龄相关的氧化应激增强了 Abeta 的作用。
