JPND: Targeting epigenetic dysregulation in the brainstem in Alzheimer's Disease (EPI-AD)

阿尔茨海默病是一种非常复杂的疾病，其病因在很大程度上仍然未知，尽管人们普遍认为遗传和环境因素都可以改变一个人的风险。2015年，英国将有超过85万人患有痴呆症，每年的护理费用超过260亿英镑。阿尔茨海默氏病占痴呆症病例的60%以上，其特征是特定脑细胞的丧失，导致越来越严重的行为和性格变化，患者失去独立性，需要更多的护理，并最终在多年不幸的痛苦后死亡。奇怪的是，这种疾病的特征是大脑中只有一些区域的脑细胞损失，一些区域在疾病的早期就受到影响，特别是大脑中涉及学习和记忆的区域，而其他区域对神经细胞损失相对具有抵抗力。虽然在了解阿尔茨海默病大脑中发生的细胞变化方面取得了很大进展，但目前可用的治疗方法只能暂时改善症状，而不能治疗潜在的疾病。这是因为当一个人开始表现出疾病的症状时，例如健忘和性格变化，阿尔茨海默病的“标志”，包括神经细胞丢失，淀粉样蛋白斑块沉积和缠结形成，已经开始在大脑中。事实上，最近的一些研究表明，这些变化可能在诊断之前已经在大脑中长达十年。在开发出真正有效的阿尔茨海默病治疗方法之前，必须回答四个关键的关键问题。首先，我们需要了解为什么这种疾病会影响某些人，而另一些人即使到了很老的年龄，仍然保持认知健康。第二，我们需要了解为什么大脑的某些区域会屈服于疾病，而其他区域似乎不那么容易受到影响。第三，我们需要确定新的疾病标志物，称为“生物标志物”，它们很容易在血液中测量，不仅能够早期诊断疾病，还能预测一个人出现症状的速度。最后，我们需要确定新的药物靶点。该项目计划将联合收割机的临床、遗传和分子数据结合起来，以更好地了解阿尔茨海默病的病因。众所周知，基因的表达和蛋白质的产生不仅依赖于一个人的特定DNA代码（他们的基因组），而且还可以通过称为“表观基因组”的额外信息来改变。表观遗传过程本质上是添加到DNA中的化学标签，并在不改变DNA序列的情况下打开和关闭基因，并且可以受到外部因素的影响，例如细胞或个体所处的环境。该项目将研究阿尔茨海默病患者脑干中两种不同化学标记（DNA甲基化和羟甲基化）的水平，以确定疾病中表观遗传改变的基因，从而代表新的干预药理学靶点。此外，我们将研究轻度认知障碍患者血液样本中基因的DNA甲基化标签水平，这些患者代表了一组有患阿尔茨海默病风险的个体，使我们能够识别预测性生物标志物，从而进行早期诊断。最后，我们将尝试使用来自阿尔茨海默病患者和年龄匹配对照的血液的诱导多能干细胞（iPSC）在阿尔茨海默病的先进实验模型系统中模拟我们的表观遗传变化。

Alzheimer's disease is a very complex disease, with its cause still largely unknown, although it is widely believed that both genetic and environmental factors can alter a person's risk. In 2015 more than 850,000 people will be living with dementia in the UK, with care costs in excess of £26 billion per year. Alzheimer's disease accounts for more than 60% of dementia cases and is characterised by the loss of specific brain cells, leading to increasingly severe behavioural and personality changes, loss of the sufferer's independence, ever greater care requirements and ultimately death after many unfortunate years of suffering. Curiously the disease is characterised by brain cell loss in only some areas of the brain with some regions affected very early in disease, particularly areas of the brain involved in learning and memory, whilst other regions are relatively resistant to nerve cell loss. Although much progress has been made in understanding the cellular changes that happen in the brain in Alzheimer's disease, the treatments currently available only temporarily improve symptoms and do not treat the underlying disease. This is because by the time a person starts displaying symptoms of the disease, such as forgetfulness and personality changes, the "hallmarks" of Alzheimer's disease, which include nerve cell loss, amyloid plaque deposition and tangle formation, have already started in the brain. In fact some recent studies have shown that these changes may have been in the brain for up to ten years prior to diagnosis. Four key pivotal questions must be answered before a truly effective treatment for Alzheimer's disease can be developed. First we need to understand why the disease affects certain individuals, whilst other people remain cognitively healthy, even into very old age. Second we need to understand why certain regions of the brain succumb to disease, whilst others seem to be far less susceptible. Third we need to identify new markers of disease, called "biomarkers" that are easy to measure in blood, and that are able to not just diagnose the disease early, but to also predict how quickly a person will develop symptoms. Finally, we need to identify new drug targets. This project plans to combine clinical, genetic and molecular data to better understand the causes of Alzheimer's disease. It is known that the expression of genes and the production of proteins relies not only on a person's specific DNA code (their genome), but can also be altered by an extra level of information called the "epigenome". Epigenetic processes are essentially chemical tags that are added to the DNA, and act to turn genes on and off, without changing the DNA sequence, and can be influenced by external factors such as the environment in which cells or individuals dwell. This project will look at levels of two different chemical tags (DNA methylation and hydroxymethylation) in the brainstem of people with Alzheimer's disease to identify genes that are epigenetically altered in disease, and could thus represent novel pharmacological targets for intervention. Further, we will look at levels of the DNA methylation tag in genes in blood samples from people with mild cognitive impairment, who represent a group of individuals at risk of developing Alzheimer's disease, to enable us to identify predictive biomarkers to allow early diagnosis. Finally we will attempt to model our epigenetic changes in an advanced experimental model system for Alzheimer's disease using induced Pluripotent Stem Cells (iPSCs) derived from the blood of Alzheimer's disease patients and age-matched controls.