Oxidative DNA Damage and Transcriptional Impairment in Brain Ageing as an Early Contributor to Cognitive Impairment

随着人口老龄化，痴呆症对个人及其家庭以及整个社会提供的护理都是一个日益严重的问题。因此，迫切需要了解脑功能下降的原因，并确定潜在的新治疗途径，既可以延缓痴呆症的进展，也可以延缓其发病，这将对痴呆症在人群中的患病率产生重大影响。大多数关于痴呆症的研究都是基于对已确诊的痴呆症患者与未确诊的痴呆症患者的比较，并且主要关注阿尔茨海默病（AD），这是痴呆症的最常见原因。然而，这并不能准确反映人口背景下的情况。MRC认知功能和衰老研究（CFAS）是一项具有人口代表性的研究，该研究表明，痴呆和非痴呆个体在老年痴呆症病理上存在重叠，这种重叠在老年痴呆症患者中增加，因此有必要确定其他导致痴呆的因素的作用。氧化应激已被证明与神经退行性疾病有关，并能破坏细胞中的多种分子，包括构成基因和编码细胞蛋白质的DNA。我们的研究表明，在老年人群中，高水平的DNA氧化损伤可能发生在一些很少或没有AD病理的个体中，这表明它可能独立于AD导致痴呆。该项目的目的是确定人群大脑中的DNA氧化损伤及其与痴呆和阿尔茨海默病进展的关系。使用允许我们分析细胞内基因表达的整体变化的方法，我们将确定氧化DNA损伤如何影响人类脑组织和实验细胞培养模型中神经细胞的细胞通路。这些研究将提供氧化损伤与神经细胞功能下降之间的联系，并为研究痴呆症的机制和潜在的治疗方法开辟新的途径。

With our ageing population, dementia is an increasing problem for individuals and their families and for the provision of care by society as a whole. There is an urgent need therefore to understand contributors to decline in brain function and to define potential new avenues for therapies, both to delay the progression of dementia and to delay its onset, which will have a major effect on dementia prevalence in the population. Most studies of dementia have been based on comparisons of individuals with established dementia to those with no dementia, and a major focus has been on Alzheimer's disease (AD), the commonest cause of dementia. However, this does not accurately reflect the situation in a population setting. The MRC Cognitive Function and Ageing Study (CFAS), a population-representative study, has shown an overlap in AD pathology between demented and non-demented individuals that increases at the oldest ages, so there is a need to define the role of other contributors to dementia. Oxidative stress has been shown to be associated with neurodegenerative diseases, and can damage a variety of molecules in cells, including DNA, which makes up genes and encodes cell proteins. Our studies have shown that, in the elderly population, high levels of DNA oxidative damage can occur in some individuals with little or no AD pathology, suggesting that it may contribute to dementia independently of AD. The purpose of this project is to determine DNA oxidative damage in the brain in the population and its relationship to dementia and the progression of AD. Using methods that allow us to analyse overall changes in the expression of genes within cells, we will then determine how oxidative DNA damage affects the cellular pathways of nerve cells in both human brain tissue and an experimental cell culture model. These studies will provide the link between oxidative damage and the decline in nerve cell function and open up novel avenues for research studies into mechanisms of dementia and potential treatments.