Bioscience for an integrated understanding of health

Category: Standard Studentships

Mapping APOE and Microglial effects on cognition across the lifespan

Primary Supervisor

Dr Sarah King – University of Sussex

Co-Supervisor(s)

Dr Diego Gomez-Nicola – University of Southampton

Summary

With an ever-increasing ageing population (by 2039 UK will have 10 million people aged over 74 (ONS)), it is becoming increasingly important to maximise the chances of staying healthy throughout life.

Cognitive decline is subject to considerable variation between individuals and APOE genotype is a major determinant of this age-related variation: The e4 allele of this gene (APOE4), carried by ~20% of UK population, has significant negative consequences for cognitive ageing even in the absence of pathology. Patterns of neurocognitive performance vary with APOE genotype across age and correlate with changes in regional brain activity. Microglial cells have a critical role in CNS homeostasis and health, clearing toxins and releasing neurotrophic factors. The regional heterogeneity of the microglial population is becoming increasingly recognised as a factor that may contribute to the susceptibility of specific brain areas (e.g. hippocampus) to damage across the lifespan. APOE contributes to the function and dysfunction of microglia, and we hypothesise that the differing cognitive profile of APOE3 and APOE4 targeted replacement mice across the life span is driven by the differing regional heterogeneity of specific microglial populations.

The student will:

  • Test the cognitive profile of APOE3 and APO4-TR mice on hippocampal-mediated and non-mediated behaviours at 3 and 12 months (e.g. spatial vs novel object recognition).
  • After cognitive testing, compare microglial cells in the hippocampi of APOE3-TR and APOE4-TR mice, using IHC and RNASeq.
  • Use pharmacological or genetic intervention to kill/modify microglial populations (informed by (2)) and test the impact on hippocampal-sensitive cognitive tests (as informed by (1)).

This project will provide an interdisciplinary training for the student, leading to expertise in both behavioural and molecular neuroscience techniques. Understanding how APOE genotype contributes to cognitive decline across the lifespan, will allow us to develop new methods of interventions to promote healthy ageing.