Using iPSC models to examine neuron–glia interactions in neurodegenerative diseases

Neurodegenerative diseases remain without effective or accessible treatments and interventions, despite their increasing global burden. Clinically, these disorders are characterised by progressive cognitive decline, behavioural changes, and loss of motor function, all of which are associated with neuronal and synaptic loss or dysfunction. Although traditionally viewed as neuron-centric, it is becoming increasingly clear that glial cells play critical roles in maintaining and regulating neuronal and synaptic health. Mounting evidence implicates glial dysregulation in both the onset and progression of neurodegenerative diseases through mechanisms such as aberrant synaptic engulfment and protein clearance, impaired homeostatic support, metabolic dysfunction, chronic inflammation, transmission of pathogenic proteins, and cellular senescence. Elucidating how disruptions in neuron-glia interactions contribute to neuronal dysfunction is therefore essential for developing effective therapies. Induced pluripotent stem cell (iPSC)-based models provide a powerful platform to investigate these interactions in human-relevant systems. Here, we will discuss recent insights into the mechanisms contributing to neurodegenerative disease that have been gained specifically from modelling neuron-glia interactions in human iPSCs.