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不清楚，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，每年的护理费用将超过260亿GB。阿尔茨海默病占痴呆症病例的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个性变化，患者丧失独立性，越来越多的护理需求，并在经历了许多不幸的岁月后最终死亡。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丢失，一些区域在疾病的早期就受到影响，特别是涉及学习和记忆的大脑区域，而其他区域则相对抵抗神经细胞丢失。尽管在了解阿尔茨海默病患者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，不能治疗潜在的疾病。这是因为当一个人开始表现出健忘和个性变化等疾病症状时，阿尔茨海默病的“特征”，包括神经细胞丢失、淀粉样斑块沉积和缠绕形成，已经在大脑中开始。事实上，最近的一些研究表明，在确诊之前，这些变化可能已经在大脑中存在了长达十年的时间。在开发出真正有效的阿尔茨海默病治疗方法之前，必须回答四个关键问题。首先，我们需要了解为什么这种疾病会影响某些人，而其他人即使到了很老的时候，也会保持认知健康。其次，我们需要了解为什么大脑的某些区域会屈服于疾病，而其他区域似乎更不容易受到疾病的影响。第三，我们需要找出新的疾病标记物，称为“生物标记物”，这种标记物很容易在血液中测量，不仅能早期诊断疾病，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。该项目计划将临床、基因和分子数据结合起来，以更好地了解阿尔茨海默病的原因。众所周知，基因的表达和蛋白质的生产不仅依赖于一个人特定的DNA代码(他们的基因组)，而且还可以通过额外的信息水平改变，称为“表观基因组”。表观遗传过程本质上是添加到DNA上的化学标签，作用是在不改变DNA序列的情况下开启和关闭基因，并可能受到外部因素的影响，如细胞或个人居住的环境。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，以确定在疾病中发生表观遗传改变的基因，从而可能成为干预的新药理学靶点。此外，我们将研究轻度认知障碍患者血液样本中DNA甲基化标签的水平，这些患者代表了一组有患阿尔茨海默病风险的个人，使我们能够识别预测生物标记物，以便进行早期诊断。最后，我们将尝试在阿尔茨海默病高级实验模型系统中模拟我们的表观遗传学变化，使用从阿尔茨海默病患者和年龄匹配的对照组的血液中提取的诱导多能干细胞(IPSCs)。

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.