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

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.

Alzheimer's disease (AD) is a neurodegenerative disease that affects brain integrity and functioning, resulting in progressive cognitive deterioration. Previous work indicates that epigenetic mechanisms including DNA (hydroxy)methylation represent critical factors in the pathogenesis of AD. Moreover, the early occurrence of various neuropsychological symptoms and novel neuropathological findings suggest a key role for the brainstem, particularly serotonin (5-HT)- and noradrenaline (NA)-specific neurons.

Therefore, we hypothesise that epigenetic dysregulation in the brainstem has a critical role in the early pathogenesis of AD and aim to elucidate the exact role of DNA (hydroxy)methylation within the brainstem in the development and progression of AD. Our objectives will be addressed within our cross-disciplinary network, through the use of established large human cohorts. The consortium will link the epigenetic profiles with cognitive dysfunction, AD-related neuropathology, gene variants regulating 5-HT and NA-function (Objectives I & II). For biomarker discovery, blood epigenetic signatures of aging individuals will be linked to subsequent cognitive decline, MCI-AD conversion and depression (Objective III). The putative signatures will also be compared to established (more invasive) biomarkers to determine their validity. By making use of iPSCs (Objective IV), the project will furthermore test whether i) neurons derived from iPSCs of AD patients develop an AD-characteristic molecular/epigenetic and cellular phenotype when exposed to AD brain extracts or glucocorticoids (GCs), and ii) epigenetic editing of candidate genes (from Objectives I and II) within 5-HT and NA neurons generated from iPSCs can reverse AD-specific phenotypes.

The comprehensive approach of this project will fill the vital gap in our understanding of the links between epigenetic dysregulation and the 5-HT and NA neurotransmitter systems in the pathophysiology of AD.

In addition to scientists interested in the aetiology of AD, the results of this project have the potential to impact on a number of other beneficiaries. These include patients suffering from AD, the pharmaceutical industry, health service providers and academic groups investigating the causes of other complex disease phenotypes. In the UK more than 850,000 people are living with dementia, with care costs in excess of £26 billion per year. Due to an increasingly ageing population, the number of cases is rising dramatically, with profound socioeconomic consequences as our healthcare systems struggle to cope. AD accounts for ~60% of cases and the current treatments temporarily alleviate some symptoms but do not modify the underlying disease process. A better understanding of the underlying mechanisms driving disease onset and progression is required to enable the design of new, more effective medications. Given the dynamic and potentially-reversible nature of the epigenome, the outputs from this research could potentially identify new targets and molecular pathways for pharmacological intervention. A number of pharmaceutical companies are actively developing "epigenetic-drugs" and could rapidly take advantage of these outputs. Another output of this research is the identification of predictive blood biomarkers for AD. By the time an individual becomes symptomatic for AD, there is already considerable neuropathology, which can appear years before the clinical diagnosis. The identification of predictive signatures in the blood would enable the diagnosis of disease many years before symptoms appear, allowing "at-risk" individuals to receive treatment before pathology has occurred.