Department of Biochemistry and Nutrition, Central Food Technological Research Institute, CSIR Unit, Mysore, India.
Neurochem Int. 2010 Apr;56(5):655-62. doi: 10.1016/j.neuint.2010.01.012. Epub 2010 Feb 1.
DNA stability and conformation are important in the life cycle of an organism. The DNA instability is postulated to be one of the risk factors for neuronal death in neurodegenerative disorders. Among all other risk factors, amyloid is one of the most important risk factor for neurodegeneration. Abeta(42) is implicated in Alzheimer's disease (AD). Studies from our lab and elsewhere have shown that Abeta(42) could cause DNA damage and alter DNA stability in vitro and there are no mechanistic studies to understand Abeta induced genomic instability under in vivo condition. The present study aims to characterize Abeta(42) induced DNA instability and also to map the changes in DNA conformation in vivo and its correlation to brain structural changes. The aged (4yr) New Zealand rabbits are intracisternally injected with Abeta(42) and are sacrificed after 25 days, when the rabbits developed AD like behavior. Genomic DNA is isolated from frontal cortex (FC), hippocampus (H) and midbrain (M) regions of Abeta(42) injected and control rabbit brain. The DNA stability parameters are analyzed. And the results showed that DNA is damaged in FC and H; where as in M, DNA is in condensed state. The DNA conformation study evidenced the presence of C-, pi- and psi-type DNA in conformations in FC, H and M of Abeta injected rabbit brain regions respectively. But in control rabbit brain, DNA is in B-conformation in all the brain regions studied. Magnetic resonance imaging (MRI) studies showed no significant changes in brain structure between control and Abeta(42) injected aged rabbit brain regions. The mechanism of Abeta(42) induced neurodegeneration through genomic instability is discussed in detail.
DNA 的稳定性和构象对于生物体的生命周期至关重要。DNA 不稳定性被认为是神经退行性疾病中神经元死亡的风险因素之一。在所有其他风险因素中，淀粉样蛋白是神经退行性变的最重要风险因素之一。β淀粉样蛋白（Abeta）与阿尔茨海默病（AD）有关。我们实验室和其他实验室的研究表明，Abeta（42）可导致 DNA 损伤，并在体外改变 DNA 稳定性，目前尚无机制研究来了解体内 Abeta 诱导的基因组不稳定性。本研究旨在描述 Abeta（42）诱导的 DNA 不稳定性，以及体内 DNA 构象的变化及其与大脑结构变化的相关性。将 aged（4 岁）新西兰兔经脑室内注射 Abeta（42），25 天后，当兔子出现 AD 样行为时处死。从 Abeta（42）注射和对照兔脑的额皮质（FC）、海马（H）和中脑（M）区域分离基因组 DNA。分析 DNA 稳定性参数。结果表明，FC 和 H 中的 DNA 受损；而在 M 中，DNA 处于凝聚状态。DNA 构象研究表明，在 Abeta 注射兔脑区域的 FC、H 和 M 中分别存在 C-、pi-和 psi 型 DNA。但在对照兔脑中，所有研究脑区的 DNA 均呈 B-构象。磁共振成像（MRI）研究表明，对照和 Abeta（42）注射的 aged 兔脑区之间的脑结构没有明显变化。详细讨论了 Abeta（42）通过基因组不稳定性诱导神经退行性变的机制。
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