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

Lead Research Organisation: University of Exeter
Department Name: Peninsula Medical School

Abstract

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 "bomarkers" 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.

Technical Summary

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.

Planned Impact

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.

Publications

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Smith AR (2019) Clinical Epigenetics in Parallel profiling of DNA methylation and hydroxymethylation highlights neuropathology-associated epigenetic variation in Alzheimer's disease.

 
Description An integrated "omics" analysis to elucidate the role of miRNAs in Alzheimer's disease
Amount £49,217 (GBP)
Funding ID ARUK-PPG2017B-021 
Organisation Alzheimer's Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 08/2017 
End 07/2019
 
Description Determining the potential utility of epigenetic modulators to treat Alzheimer's disease: A collaboration between Exeter and Oxford ARUK Network Centres and the Oxford DDI
Amount £98,360 (GBP)
Funding ID ARUK-NCG2017A-5 
Organisation Alzheimer's Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2017 
End 02/2019
 
Description Major project grant
Amount € 1,431,308 (EUR)
Organisation EU Joint Programme - Neurodegenerative Disease Research (JPND) 
Sector Public
Country European Union (EU)
Start 07/2016 
End 06/2019
 
Description New JPco-fuND application 2019 
Organisation Maastricht University (UM)
Country Netherlands 
Sector Academic/University 
PI Contribution New JPco-fuND application submitted to continue partnership
Collaborator Contribution We have submitted an application that will be to continue our previous JPco-fuND partnership, but moving to the next level by performing integrative multi-omic studies
Impact Application to JPco-fuND submitted
Start Year 2016
 
Description ARUK Annual Scientific meeting 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Postgraduate students
Results and Impact Annual scientific open day for ARUK South West Network
Year(s) Of Engagement Activity 2015,2016,2017,2018
 
Description 2016 MRC Prion Unit, UCL Institute of Neurology, UK (Invited Speaker) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact Invited speaker at UCL Prion unit
Year(s) Of Engagement Activity 2016
 
Description 2017 Alzheimer's Research UK National Conference, Aberdeen, UK (Invited Speaker) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact Invited speaker at Alzheimer's Research UK annual conference in Aderdeen
Year(s) Of Engagement Activity 2017
 
Description 2017 Alzheimer's Society National Conference, London, UK (Invited Speaker) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Invited speaker at Alzheimer's Society annual meeting in London
Year(s) Of Engagement Activity 2017
 
Description 2017 Arch Education, Hong Kong University, Hong Kong (Invited Speaker) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Invited speaker to discuss research and encourage students to undertake Medical sciences degree
Year(s) Of Engagement Activity 2017
 
Description 2017 Bioinformatics and Genomics Group, University of Southampton, UK (Invited Speaker) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact Invited speaker at Southampton University
Year(s) Of Engagement Activity 2017
 
Description 2017 British Neuroscience Association Annual Meeting, Birmingham, UK (Invited Speaker) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Invited speaker at BNA meeting to discuss research
Year(s) Of Engagement Activity 2017
 
Description 2017 Department of Neuroscience, University of Sheffield, UK (Invited Speaker) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Industry/Business
Results and Impact Invited speaker in Sheffield and to discuss new collaborations
Year(s) Of Engagement Activity 2017
 
Description 2018 Department of Clinical Sciences, University of Cambridge, UK (Invited Speaker) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact Invited speaker at Cambridge University
Year(s) Of Engagement Activity 2018
 
Description 2018 School of Medicine and Psychology, Cardiff University, UK (Invited Speaker) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact Invited speaker at Cardiff University to allow discussions about new collaborations
Year(s) Of Engagement Activity 2018
 
Description 2018 School of Pharmacy, University of Reading, UK (Invited Speaker) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact Invited speaker at Reading University to allow new collaborations
Year(s) Of Engagement Activity 2018
 
Description 2019 British Neuropathological Society bi-annual meeting, London, UK (Invited Speaker) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Invited speaker at British Neuropathological Society meeting in London UK
Year(s) Of Engagement Activity 2019
 
Description 2019 Lundbeck (Pharma), Copenhagen, Denmark (Invited Speaker) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact Invited speaker at Lunbeck in Copenhagen to discuss potential collaborations
Year(s) Of Engagement Activity 2019
 
Description 2019 UK Dementia Research Institute, Imperial College London, UK (Invited Speaker) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact Invited talk at UK DRI at Imperial to allow discussions about potential collaborations
Year(s) Of Engagement Activity 2019
 
Description ARUK Annual Public Open day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact ARUK annual open day attendance and speaking to public
Year(s) Of Engagement Activity 2015,2016,2017,2018