Using stem cells to model the molecular mechanisms of exercise for dementia prevention

About the Project

Alzheimer’s disease (AD) is the most common cause of dementia, affecting millions worldwide and placing an increasing burden on patients, families and healthcare systems. While emerging therapeutics targeting amyloid pathology show promise, treatment options remain limited and do not address all aspects of disease progression. At the same time, strong epidemiological evidence suggests that lifestyle factors, particularly regular physical activity, can substantially reduce dementia risk and enhance cognitive function. However, the biological mechanisms by which exercise exerts these beneficial effects are not fully understood. One hypothesis is that skeletal muscle communicates with the brain through a cocktail of secreted proteins, peptides and extracellular vesicles (collectively termed “exerkines”) that can modulate neurotrophic pathways, inflammation and metabolic function. Yet much of this signalling remains poorly characterised, and almost nothing is known about how these pathways may differ in individuals carrying AD-causing genetic mutations. Human-relevant models capable of capturing muscle biology, contraction and secretion are essential to address these gaps. This PhD studentship focuses on developing and applying novel human iPSC-derived skeletal muscle model to explore how muscle-secreted factors influence AD-relevant brain cell function.

Aims and Approach

The overarching aim is to establish a physiologically relevant human muscle platform and use it to test how muscle-derived signals affect amyloid precursor protein (APP) processing, inflammatory pathways and metabolic resilience in human iPSC-derived neurons and astrocytes.

Key objectives include:

1. Generation and characterisation of iPSC-derived myotubes.
   Using self-assembling functionalised hydrogel scaffolds you will differentiate iPSCs into mature, contractile myotubes. You will characterise myofibre development, contractility, calcium handling and expression of key structural and metabolic markers in both healthy and familial AD mutation lines.
2. Profiling the muscle secretome and metabolic function.
   You will quantify secreted proteins, peptides and extracellular vesicles under resting and stimulated (e.g. electrically induced contraction) conditions. This will include analysis of cargo relevant to neurotrophic signalling, metabolism and APP-related pathways.
3. Integrating muscle and brain models.
   Using complementary systems including conditioned medium transfer, transwell co-culture incorporating a human microvascular endothelial “blood–brain barrier” layer, and microfluidic devices, you will deliver muscle-derived signals to iPSC-derived neurons and astrocytes. Downstream effects on APP processing, neuroinflammation, mitochondrial function and vesicle uptake will be measured using imaging, biochemical assays and live-cell analyses.

Training and Environment

You will join an interdisciplinary team at the University of Birmingham working at the interface of exercise biology, neurodegeneration, stem cell modelling and bioengineering. Full training will be provided in iPSC culture and differentiation, extracellular vesicle isolation, quantitative microscopy, molecular assays and fluidic-device-based co-culture systems. Close collaboration with an industry partner will offer additional experience in biomaterials and translational technology development.

Expected Outcomes and Impact

This project will deliver a novel human iPSC-derived muscle platform specifically designed to interrogate muscle–brain signalling in Alzheimer’s disease. By identifying the key muscle-derived factors and mechanisms that influence AD-related cellular vulnerability, the research will advance our understanding of how physical activity promotes brain health. Ultimately, these insights could inform optimised exercise prescriptions, new biomarkers of brain–muscle communication and potential “exercise-mimetic” therapeutic strategies for individuals unable to engage in strenuous activity.

Funding Notes

This is for students considering self-funding their PhD studies. Bench fees (for lab work only) are funded by the Supervisors existing funding.