TC9 - Investigating the effect of post translational modifications on Rare ApoE variants

• Funding – Tricia Cohen Prize funded 4-year studentship, providing tuition fees, training/research costs and an annual tax free stipend of £21,342
• Start Date – September 2026
• Applicants are expected to have a degree (equivalent of Honours or Masters) in a relevant discipline.

Alzheimer’s Disease (AD) is one of the most prevalent neurodegenerative diseases in the UK causing progressive memory decline and impacting approximately 1 in 14 people over the age of 65. Apolipoprotein E (ApoE) is the greatest genetic modulator of AD with three common variants found in the population. The ApoE3 variant is considered to be neutral while the ApoE4 variant increases the risk of AD 3-12 fold and the ApoE2 variant decreases AD risk dramatically. These common variants have been studied for many years and it has been found that ApoE impacts several biological processes predisposing the brain to AD. 

These ApoE isoforms differ by a single amino acid; this small change presumably alters the conformation of the protein, altering its activity in many biological pathways resulting in both gain and loss of function. Work in the field has thus far been focused on the detrimental role that ApoE4 plays in the brain, with current therapeutical strategies based on removing it. Much less is known about how the ApoE2 variant is protective. Rare variants of ApoE have recently been discovered that similarly are single amino acid changes and clearly impact the risk for AD likely due either to changes in structural or receptor binding properties Several rare protective APOE variants have been recently discovered including APOE3 Jacksonville (V236E), APOE4 R251G, and most excitingly of all APOE3 Christchurch (R136S) which is thought to have prevented AD in a rare familial version of the disease. These variants are also single amino acid changes and studying these variants in greater depth will allow us to test the hypotheses that ApoE2 and rare protective variants have different structural properties compared to ApoE4. In particular, ApoE isoforms show differences in glycosylation and sialylation patterns although how this important post translational modification impacts the function of both the common and rare APOE variants is unknown. These structural changes lead to differences in receptor binding and differences in biological effects on neuroinflammatory systems. Understanding these could guide the design of therapeutic strategies targeting ApoE in AD

In this proposal we plan to investigate the structural, receptor binding, and functional properties of these rare variants of ApoE using astrocyte, hepatocyte, and microglial derived ApoE. These different cell types differentially glycosylated APOE. We will also investigate the impact of these rare ApoE variants on neuroinflammation and amyloid aggregation and uptake using in house assays. We will then tie these results together to give greater understanding to the mechanisms by how this important element of the ApoE protein impacts the downstream processes. By studying these proteins in a wide battery of tests we hope to improve understanding of how each element of ApoE and the differences conferred by these single amino acid changes impacts the processes that increase or decrease AD risk.

Our research community thrives on the diversity of students and staff which helps to make the University of Dundee a UK university of choice for postgraduate research.  We welcome applications from all talented individuals and are committed to widening access to those who have the ability and potential to benefit from higher education.