Post-mortem characterisation and organotypic culture modelling of DNA damage in Alzheimer’s disease and dementia with Lewy bodies

Neurodegenerative dementias, such as Alzheimer’s disease and Dementia with Lewy bodies are growing medical and social issues. Whilst recent advancements in Alzheimer’s disease therapies have been hailed as clinical breakthroughs, the reality is that meaningful treatment for these diseases remain lacking. The foremost challenge in developing effective disease treatments is the identification and comprehension of toxic mechanisms which underlie the cellular dysfunctions causative in neuronal dysfunction and thus cognitive impairments. Recently my lab and others have discovered excessive genomic DNA damage as an early occurring insult in various neurodegenerative diseases. This damage has the potential to disrupt many cellular functions, activate pathways of cell death and may also contribute to neuroinflammation and protein aggregation. Yet it remains unclear how such damage relates to the pathological hallmarks of each disease (Aβ, tau, alpha-synuclein pathology). Recently we have demonstrated that in dementia with Lewy bodies, a novel nuclear alpha-synuclein pathology occurs which may induce genomic DNA damage. Whether such similar processes occur with Aβ and tau in Alzheimer’s disease remains to be determined.

We now wish to further characterise this genomic DNA damage in both Alzheimer’s disease and Dementia with Lewy bodies, such that we will gain an understanding of the commonalities and differences in DNA damage between these diseases. The project will utilise post-mortem human tissue to examine the regional occurrence of DNA damage markers alongside established hallmark and novel nuclear pathology via tissue microarray immunohistochemistry, western blot and potentially mass spectrometry. Pathology induced DNA damage will be modelled via living organotypic slice cultures in order to generate a platform for further mechanistic investigation and critically for drug discovery and development.

Throughout the project, a collaborative relationship will be in place between the University of Dundee and Newcastle University, with the potential for short visits to Newcastle for training in the use of living human organotypic cultures. Equally the student will join a growing environment of neurodegenerative research at the School of Medicine in Dundee, with integration to cross-laboratory group meetings, discussions, and peer groups.

In order to promote career progression and future independence, support and guidance toward developing research and presentation skills will be offered as will opportunities to attend and present at relevant national conferences.

It is essential that candidates have an interest in neurodegenerative diseases, with a solid basis of neuroscience principles, and are keen to learn techniques in post-mortem human tissue examination, advanced microscopy, and tissue culture. Successful candidates will have received or anticipate a 1st class or upper 2nd class degree (or equivalent) in a relevant biomedical sciences degree programme. It would be beneficial for candidates to have a MSc/MSci level qualification, to have experience in one or more of the relevant techniques and having already worked on projects relating to Alzheimer’s disease and/or dementia with Lewy bodies.