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Discerning the Impact of Perfluorinated Pollutants on Sporadic Alzheimer's Disease Onset through Direct and Indirect Modulation of Beta-Secretase Activity


   Faculty of Life Sciences

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  Dr Clare Peyton, Dr Ritchie Williamson, Dr Richard Telford  No more applications being accepted  Funded PhD Project (UK Students Only)

About the Project

Are you interested in how environmental pollutants may play a role in Alzheimer’s disease?

“Forever chemicals” is a term used for a class of polyfluorinated chemical pollutants that have been linked to a wide range of diseases due to their long environmental and biological half-lives and have been classified by the UK and UNEP as a persistent organic pollutant. This problem of “forever chemicals” is compounded by their extensive use across a wide range of commercial sectors, e.g. waterproof fabrics, anti-stick technology, and to-date they have been detected in blood, muscle, kidney, liver, heart and brain tissue. Accumulation of these chemicals in the brain has been linked to neurotoxicity and cognitive impairment.  At the same time, there are reports that pollution is linked to dementia incidence and there is growing evidence that environmental toxins may be linked to increased levels of amyloid-beta(1-42), a cleavage product from the amyloid precursor protein (APP) and the key component in the amyloid plaques found in Alzheimer's disease. Further, there is evidence that expression of APP is elevated in response to environmental toxins. Over 95% of Alzheimer’s disease cases observed in people aged 65 and over are sporadic in nature without a strong genetic component to explain the disease onset, implying a strong environmental factor could be key to understanding sporadic AD cases. Yet, little knowledge exists to explain the observations of pollutant impact on dementia and amyloid-beta formation. Hence, this project will examine if “forever chemicals”, as a class of persistent pollutants, could be contributing to, or triggering, Alzheimer's disease through interrupting APP processing.

The project is highly interdisciplinary using a combination of experimental and computational techniques and the student will be trained in the techniques required. We will focus a key biological target involved in APP processing called beta-secretase, an enzyme that cleaves APP and produces the amyloidogenic amyloid-beta(1-42) and which is also reported to be overactive or overexpressed in AD patients. The project will examine if accumulated “forever chemicals” in AD brain tissue could be increasing amyloid-beta production via modulating beta-secretase activity, either directly or indirectly through interacting with other APP processing proteins. Molecular biology will be used to identify the presence of “forever chemicals” in postmortem brain tissue from sporadic AD cases and cell culture studies will be used to determine the neurotoxicity of these chemicals and confirm the impact the “forever chemicals” have upon the expression and activity of beta-secretase and related proteins. NMR spectroscopy and computational simulations will be used to structurally characterize interactions and conformational changes between the “forever chemicals” and beta-secretase and other AD-related proteins. The simulations will provide dynamic information as well as provide atomic level detail of the changes and interactions that underpin the behaviour of “forever chemicals” within APP processing.

About You

You will have an undergraduate degree in a relevant life sciences subject and have been awarded a 2.1 or above. You will be highly motivated to learn a range of complementary techniques at the interface of chemistry and biology. Previous experience of computational modelling or the use of Linux is desirable but is not required as all training will be given, however, you should be committed to learning and using computational methods alongside experimental techniques. You should also possess strong written and oral communication skills and, due to the interdisciplinary nature of the project, will need to be well organised.

Anticipated Start Date

October 2022

How to apply

Formal applications should be made via the University of Bradford web site.


Funding Notes

Funds are available to cover the tuition fees and consumables (bench fees) required for this project, however no stipend to cover living costs is provided. Applications are invited from UK citizens and those settled on the UK. EU/International student applications are welcome but will require additional funding

References

1. Masters, C., Bateman, R., Blennow, K. et al. (2015) Alzheimer's disease. Nat Rev Dis Primers 1,15056
2. Chin-Chan M, Navarro-Yepes J, Quintanilla-Vega B (2015) Environmental pollutants as risk factors for neurodegenerative disorders: Alzheimer and Parkinson diseases, Front. Cell. Neurosci. 9:124
3. Syeda T, Cannon JR (2021) Environmental exposures and the etiopathogenesis of Alzheimer's disease: The potential role of BACE1 as a critical neurotoxic target, J. Biochem. Mol. Toxic. 35:1-15
4. Cao Y, Ng C (2021) Absorption, distribution, and toxicity of per- and polyfluoroalkyl substances (PFAS) in the brain: a review, Environ. Sci.: Processes Impacts, 23: 1623-1640
5. Jazvinscak JM, Hof P, Simic G (2015) Ceramides in Alzheimer's Disease: Key Mediators of Neuronal Apoptosis Induced by Oxidative Stress and Aβ Accumulation, Oxid. Med. Cell. Longevity, 2015: Article ID 346783,

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