Characterising a new neuroimmune pathway to treat Alzheimer’s disease. MRC GW4 BioMed DTP PhD studentship 2025/26 Entry,

About the GW4 BioMed2 Doctoral Training Partnership

The partnership brings together the Universities of Bath, Bristol, Cardiff (lead) and Exeter to develop the next generation of biomedical researchers. Students will have access to the combined research strengths, training expertise and resources of the four research-intensive universities, with opportunities to participate in interdisciplinary and ‘team science’. The DTP already has over 90 studentships over 6 cohorts in its first phase, along with 58 students over 3 cohorts in its second phase.

Project Information

Research Theme:

Neuroscience & Mental Health

Summary:

Microglia are brain-resident immune cells. Alongside conventional molecular signals, the latest research suggests that specific patterns of brain activity can control microglia function. We have found that a type of brain activity normally activated during cognition (called gamma oscillations) signals to microglia via a receptor subgroup, which may drive a neuroprotective response. Using a novel experimental assay developed by our lab, this project will uncover how this signalling works to reveal new drug targets for treating conditions where immune systems in the brain malfunction, such as in Alzheimer’s disease.

Main Description: 

Microglia are brain-resident immune cells that provide the main form of defence against neuropathology. It is well known that there is dynamic crosstalk between microglia and neuronal cells that maintains brain homeostasis and coordinates neuroimmune responses. Recent studies, however, have identified a new form of neuron-microglia communication driven by rhythmic neuronal activity.

Communication between neurons generates rhythmic patterns of electrical brain activity, called neuronal oscillations. Studies have revealed that neuronal oscillations around 40 Hz – called gamma oscillations – generate a signal that regulates microglia function (PMID: 31076275). Specifically, gamma oscillations induce a homeostatic and neuroprotective immune response linked to enhanced microglia surveillance and phagocytosis that can clear pathological proteins (like amyloid-β) in mouse models of Alzheimer’s disease (AD) (PMID: 27929004).

This is important because impaired gamma oscillations and abnormal microglia function are cardinal features of neurodegenerative diseases like AD, thereby raising the tantalising possibility that these diseases could be treated by triggering Gamma-Activity Induced Neuron-microglia Signalling (hereinafter, GAINS).

However, very little is known about how GAINS works due to a lack of tractable models of this phenomenon. To this end, we have developed a new model of GAINS in ex vivo mouse brain slices and have used it to discover that GAINS occurs via colony stimulating factor 1 receptors (CSF1R), which are expressed by microglia, and via nuclear factor kappa B (NFκB) pathway signalling (manuscript in prep.). Excitingly, molecular targets of CSF1Rs and NFκB overlap with signalling pathways linked to AD risk genes (PMID: 24951455, PMID: 29312321) and targets of AD medicines in clinical trial (e.g. NCT05744401).

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