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

大脑衰老过程中的氧化 DNA 损伤和转录损伤是导致认知障碍的早期因素

• 批准号: MR/J004308/1
• 负责人: Stephen Wharton
• 金额: $ 52.69万
• 依托单位: University of Sheffield
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FJ004308%2F1
• 关键词: Oxidative; DNA; Damage; Transcriptional; Impairment

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.

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，迫切需要了解导致脑功能下降的因素，并确定潜在的新疗法途径，以延缓痴呆症的进展和延迟其发作，这将对人群中的痴呆症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患有痴呆症的个体与没有痴呆症的个体进行比较，主要关注的是阿尔茨海默病（AD），这是痴呆症最常见的原因。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）是一项人群代表性研究，已显示痴呆和非痴呆个体之间的AD病理学重叠在最老的年龄增加，因此需要定义痴呆的其他贡献者的作用。氧化应激已被证明与神经退行性疾病有关，并且可以破坏细胞中的各种分子，包括DNA，其构成基因并编码细胞蛋白质。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而导致痴呆。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AD进展的关系。使用使我们能够分析细胞内基因表达的总体变化的方法，我们将确定氧化DNA损伤如何影响人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，并为痴呆症机制和潜在治疗方法的研究开辟新的途径。

项目成果

Expression microdissection isolation of enriched cell populations from archival brain tissue.

从档案脑组织中表达显微解剖分离富集的细胞群。

• DOI: 10.1016/j.jneumeth.2016.05.007
• 发表时间: 2016
• 期刊: Journal of neuroscience methods
• 影响因子: 3
• 作者: Appleby-Mallinder C

Alpha-synuclein mRNA expression in oligodendrocytes in MSA.

• DOI: 10.1002/glia.22653
• 发表时间: 2014-06
• 期刊: GLIA
• 影响因子: 6.2
• 作者: Asi, Yasmine T.;Simpson, Julie E.;Heath, Paul R.;Wharton, Stephen B.;Lees, Andrew J.;Revesz, Tamas;Houlden, Henry;Holton, Janice L.
• 通讯作者: Holton, Janice L.

Type 2 diabetes mellitus-associated transcriptome alterations in cortical neurones and associated neurovascular unit cells in the ageing brain.

• DOI: 10.1186/s40478-020-01109-y
• 发表时间: 2021-01-06
• 期刊: Acta neuropathologica communications
• 影响因子: 7.1
• 作者: Bury JJ;Chambers A;Heath PR;Ince PG;Shaw PJ;Matthews FE;Brayne C;Simpson JE;Wharton SB;Cognitive Function and Ageing Study
• 通讯作者: Cognitive Function and Ageing Study

Metallothionein-I/II expression associates with the astrocyte DNA damage response and not Alzheimer-type pathology in the ageing brain

金属硫蛋白-I/II 表达与星形胶质细胞 DNA 损伤反应相关，但与衰老大脑中的阿尔茨海默病型病理无关

• DOI: 10.17863/cam.30557
• 发表时间: 2018
• 作者: Brayne C