Ageing is the strongest risk factor for neurodegenerative diseases such as Alzheimer's disease (AD). Microglia, the brain's resident macrophages, are uniquely long-lived cells that regulate neurodevelopment, homeostasis, and repair. Unlike neurons or astrocytes, microglia exhibit innate immune memory, meaning that even subtle early-life challenges can prime them for exaggerated inflammatory responses later in life. In the ageing brain, this "primed" state evolves into a dysfunctional and senescent phenotype, characterized by impaired migration and phagocytosis, chronic inflammation, and secretion of neurotoxic mediators. Genome-wide association studies have identified microglial genes (e.g., CD33, TREM2, APOE) as key risk factors for late-onset AD, highlighting their central role in disease pathogenesis.
Recent studies in mouse models demonstrate that microglia are the dominant cellular drivers of age-related neurodegeneration. Chronic activation and sustained proliferation push them towards senescence, defined by replicative exhaustion, loss of regenerative capacity, and a senescence-associated secretory phenotype (SASP). Senescent microglia release inflammatory cytokines (IL-6, TNF, chemokines) that amplify neuronal injury and synaptic dysfunction. Thus, microglial senescence is emerging as both a hallmark and a driver of neurodegeneration.
Currently, it is critical to target microglia senescence for the treatment of neurodegenerative diseases. Our established senescence microglia cell model has been used for the drug screening and new drug discovery. Extracellular vesicles derived from induced pluripotent stem cell-derived mesenchymal stem cells (iMSC-EVs) are a promising new approach. Our preliminary data demonstrate that iMSC-EVs strongly suppress microglial production of proinflammatory cytokines (IL-1?, TNF?, IL-6) in vitro, suggesting they may counteract senescence and restore microglial homeostatic functions. If validated, iMSC-EVs could represent a scalable, non-cellular therapeutic platform for age-related neurodegeneration.
This is an exciting opportunity for a fully-funded fixed-term (one year) research associate to work full time to advance our current human inflammatory-microglia in vitro ageing model for use in drug screening in the department of Life Science, at Manchester Met University. This project will involve working with scientists from the Ravan Bio research team.
The Role:
The role will involve culturing and differentiating human iPSCs into monocytes/macrophages, microglia and MSCs with our already established protocols and set in vitro inflammatory microglia ageing model with which relevant anti-ageing drugs and iMSCs-EVs will be validated. We are looking for someone with suitable knowledge and skill of iPSCs culture and differentiation into MSCs and microglia. Knowledge of immunology and its relation to inflammation and disease is desirable. This role will also involve presenting progress reports with our collaborators in the Rivan Bio.
Other duties and responsibilities include:
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