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

Lead Research Organisation: University of Sheffield
Department Name: Neurosciences

Abstract

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.

Technical Summary

Oxidative stress is important in brain ageing and Alzheimer's disease (AD) but the relationship to cellular dysfunction and AD progression remains unclear. In a population-representative autopsy-brain sample from the MRC Cognitive Function and Ageing Study (CFAS), we have shown that oxidative stress and DNA damage occur in some individuals with little AD-pathology, suggesting that oxidative stress contributes to cognitive decline by promoting neuronal dysfunction in some individuals independently of AD. AD pathology does not explain all of dementia in a population setting, particularly in the oldest individuals and current approaches based on removing AD molecular pathology have had limited success, suggesting an urgent need to understand the role of "non-classical" cellular pathologies. We propose that chronic oxidative DNA damage may impair neuronal function by altering the neuronal transcriptome, by down-regulation of transcription and by induction of senescence mechanisms. At a population level we propose that neuronal dysfunction due to oxidative DNA damage explains a proportion of dementia, especially in the oldest old. We plan to determine the variation in oxidative DNA damage, particularly in individuals in the population without AD using the CFAS population-neuropathology cohort. We will determine the effect of oxidative DNA damage on the neuron in both CFAS and in a neuronal culture system and using markers of senescence and microarray gene-expression analysis to determine the effect on transcription. Bioinformatics approaches will allow determination of the effect of chronic oxidative stress on cellular pathways, whist time-course analysis in the cells will allow determination of how the neuronal response changes. This study will define the contribution of oxidative stress to dementia at a population level and identify altered cellular pathways reflecting neuronal injury and adaptation response that will lead to novel avenues for investigation.

Planned Impact

At present the focus of dementia research is on classical pathological lesions, such as neurofibrillary tangles and plaques and the associated abnormal proteins, beta-amyloid and tau. These remain important targets, but the fact that these lesions do not explain all dementia in a population setting and the lack of success of current therapies that target these proteins demonstrate a need to understand non-classical markers. This project will help to define the role of oxidative stress in age-related cognitive impairment in a population setting and the cellular link between oxidative neuronal damage and neuronal dysfunction. This may aid in explaining the deficit in pathological models of dementia, especially in the oldest old, the demographic group in which AD pathology is most poorly predictive of dementia and in which most cases of dementia occur. Understanding oxidative stress and how it relates to the progression of AD pathology is itself important to targeting this therapeutically and in preventive measures to reduce cognitive impairment in a population setting. Defining how neuronal cell pathways respond to oxidative stress will identify potential novel avenues for therapies targeted against specific pathways and for biomarker development. In addition to the results from this work, the study will generate data from which novel specific hypotheses will be developed for further functional studies. The population-based data on the CFAS cohort will be archived in the CFAS database. This will be available to future studies in CFAS; the availability of this rich, population-representative set of pathological and molecular data is one of the strengths of CFAS. In addition, the bioinformatics data on both the neurons laser-captured from CFAS cases and form the cell culture work will be deposited in an on-line gene expression database, further adding value to the study by making this extensive data available for bioinformatics studies by other workers.

Publications

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Al-Mashhadi S (2015) Oxidative Glial Cell Damage Associated with White Matter Lesions in the Aging Human Brain. in Brain pathology (Zurich, Switzerland)

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Appleby-Mallinder C (2016) Expression microdissection isolation of enriched cell populations from archival brain tissue. in Journal of neuroscience methods

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Garwood C (2013) Calcium dysregulation in relation to Alzheimer-type pathology in the ageing brain. in Neuropathology and applied neurobiology

 
Description ARUK PhD Scholarship
Amount £87,900 (GBP)
Funding ID ARUK-PhD2016-1 
Organisation Alzheimer's Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2016 
End 08/2019
 
Description BNS Small Grant Scheme - Oxidative damage to nucleic acids in MND
Amount £5,000 (GBP)
Organisation British Neuropathological Society 
Sector Learned Society
Country United Kingdom
Start  
 
Description Interdisciplinary research grant
Amount £237,984 (GBP)
Funding ID ARUK-IRG2014-10 
Organisation Alzheimer's Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2014 
End 12/2016
 
Description Major project grant - Gene based therapies for frontotemporal dementia.
Amount £244,661 (GBP)
Funding ID PG2018B-005) 
Organisation Alzheimer's Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 02/2019 
End 01/2022
 
Description PhD Scholarship
Amount £84,450 (GBP)
Funding ID ARUK-PhD2016-5 
Organisation Alzheimer's Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2016 
End 08/2019
 
Description Preparatory clinical research fellowship
Amount £69,998 (GBP)
Funding ID ARUK-PCRF2016A-1 
Organisation Alzheimer's Research UK 
Department Alzheimers Research UK, Cambridge
Sector Charity/Non Profit
Country United Kingdom
Start 09/2016 
End 09/2017
 
Description Project grant
Amount £225,718 (GBP)
Organisation Alzheimer’s Society 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2015 
End 09/2018
 
Description Project grant Epidemiological neuropathology of dementia in the elderly
Amount £332,764 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start  
 
Description Project grant. Basis of post stroke dementia
Amount £378,751 (GBP)
Funding ID 386 
Organisation Alzheimer’s Society 
Sector Charity/Non Profit
Country United Kingdom
Start 02/2018 
End 01/2021
 
Title Development of immuno-directed laser capture microdissection. 
Description Protocols for cell-type specific laser capture in the CNS. 
Type Of Material Technology assay or reagent 
Year Produced 2018 
Provided To Others? Yes  
Impact Several papers over the years, most recently brought together in a methods chapter Simpson JE, Wharton SB, Heath PR. Immuno-laser-capture microdissection for the isolation of enriched glial populations from frozen post-mortem human brain. In: Murray G (eds) Laser Capture Microdissection. Methods in Molecular Biology vol 1723; pp273-284, Humana Press, New York, NY 
 
Title Gene expression microarray data associated with neuronal DNA damage 
Description Gene expression data deposited in the Gene Expression Omnibus, accession number GSE66333 
Type Of Material Physiological assessment or outcome measure 
Year Produced 2016 
Provided To Others? Yes  
Impact Availability of data to bioinformatics community. 
 
Description A Cellular Pathology and Gene Expression Approach to Understand the Basis of Progressive Dementia Occurring After Stroke 
Organisation Newcastle University
Country United Kingdom 
Sector Academic/University 
PI Contribution Joint study of post stroke dementia. We will provide laser capture and gene expression analysis.
Collaborator Contribution Collaboration has just begun.
Impact Just started
Start Year 2018
 
Description Defective nutrient signalling and dementia: an epidemiological neuropathology approach 
Organisation Newcastle University
Country United Kingdom 
Sector Academic/University 
PI Contribution Pathological analysis of CFAS tissue studying effects of diabetes on the brain.
Collaborator Contribution Tissue analysis.
Impact Conference presentations.
Start Year 2015
 
Description Defective nutrient signalling and dementia: an epidemiological neuropathology approach 
Organisation University of Cambridge
Department Cambridge Institute of Public Health
Country United Kingdom 
Sector Academic/University 
PI Contribution Pathological analysis of CFAS tissue studying effects of diabetes on the brain.
Collaborator Contribution Tissue analysis.
Impact Conference presentations.
Start Year 2015
 
Description Neurovascular dysfunction in Alzheimer's disease: the search for early biomarkers 
Organisation University of Sheffield
Department Department of Psychology
Country United Kingdom 
Sector Academic/University 
PI Contribution Collaboration with Psychology bringing together our tissue expertise and linking to physiological analysis.
Collaborator Contribution Tissue analysis, laser capture and gene expression microarrays.
Impact Review paper detailed in pulications.
Start Year 2014
 
Description Role of microRNAs in ageing at the blood brain barrier 
Organisation Open University
Country United Kingdom 
Sector Academic/University 
PI Contribution Joint two centre grant. Our centre focuses on human tissue based studies.
Collaborator Contribution Complementary studies form our collaborators at the OU, led by Dr Ignacio Romero, focus on experimental work
Impact New grant funding from BBSRC to both centres
Start Year 2013
 
Description ARUK lab tour for lay group. 
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 Public/other audiences
Results and Impact Lab tour and talks informing members of public about our research
Year(s) Of Engagement Activity 2018
 
Description Alzheimer Society Local Group Meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Member of out group spoke about our dementia research predominantly to dementia support workers.

Better public information
Year(s) Of Engagement Activity 2014
 
Description Alzheimers Research Network Volunteers Visit 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Supporters
Results and Impact Attendance by a group of lay monitors. Presented talks in relation to our projects and lab visit. Opportunities for informal discussion and advice from the lay members.
Year(s) Of Engagement Activity 2017
 
Description Blog post 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Release of blog post about our Alz Soc funded diabetes grant, written by the post doc.
Year(s) Of Engagement Activity 2017
 
Description Build up of DNA damage in nerve cells can lead to dementia. 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Steve Wharton Press release on Sheffield University website (www.shef.ac.uk) 26 June 2015
Year(s) Of Engagement Activity 2015
 
Description Dementia Futures Conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Conference designed to present results on dementia to lay public. 3 of our group's PhD students presented.
Year(s) Of Engagement Activity 2018
 
Description Dr Garwood presentation at Festival of Science and Engineering Your amazing brain 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Schools
Results and Impact Stimulated interest in children

Questions
Year(s) Of Engagement Activity 2015
 
Description Hosted laboratory visit for lay guests of the ARUK 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Lay guests and potential donors to ARUK were informed of our work on astrocytes.

Unknown at present
Year(s) Of Engagement Activity 2013
 
Description Invited speaker British Neuroscience Association Symposium 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Generate questions and discussion. Improved professional relationships that might lead to collaboration.

Communication both immediately after and by email
Year(s) Of Engagement Activity 2015
 
Description Journal promotion of one of our papers 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Promotion of our article on neuronal DNA damage response associated signalling changes.. by the publisher, Wiley to coincide with National Alzheimer's Awareness month.
Year(s) Of Engagement Activity 2016
 
Description Radio interview by Dr Claire Garwood on our group's work, BBC Radio Sheffield 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Media (as a channel to the public)
Results and Impact Informed public via radio

Not formally assessed.
Year(s) Of Engagement Activity 2015
 
Description Research Network volunteer visit (Alz Soc) Aug 2017 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Visit of Alz Soc research network volunteer. Presented the research work of our group.
Year(s) Of Engagement Activity 2017
 
Description SITraN Open Day 
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 Public/other audiences
Results and Impact Institute open day with range of talks
Year(s) Of Engagement Activity 2018
 
Description SITraN Open Day July 2014 
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 Open day at SITraN allowing lay persons to look at work on neurodegeneration, in including dementia in Sheffield.

Public information and interest in donations
Year(s) Of Engagement Activity 2014
 
Description Short film about dementia research in Sheffield 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Claire Garwood received funding from the Engaged Curriculum to produce a short film about the broad range of dementia research at the University of Sheffield.
Year(s) Of Engagement Activity 2015
 
Description Talk on diabetes at Alz Soc conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Talk "Advanced glycosylated end-products as markers of diabetes in the Alzheimer's brain.
Year(s) Of Engagement Activity 2017
 
Description Talk to Ignite Academy Event 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Talk given by member of our group "Astrocytes:Guardians of the Brain"

Better public information
Year(s) Of Engagement Activity 2014
 
Description Visit by Alzheimer's Society network volunteers 
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 Supporters
Results and Impact Stephen Wharton Organised visit by Alzheimer's Society network volunteers. Nov 10 2015. 3 visitors - meet the group, 2 talks and lab tour.
Year(s) Of Engagement Activity 2015
 
Description Workshops in primary schools 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Claire Garwood, Laura Ratcliffe and Irina Villasenor. Sheffield Festival of Science and Engineering. 3 Half day workshops in local primary schools "Your Amazing Brain".
Year(s) Of Engagement Activity 2015