Description
- Abstract:
- Despite decades of research, Alzheimer’s disease (AD) remains a severe public health crisis accounting for 60-80% of dementia cases worldwide. Growing evidence implicating microglia dysfunction in the pathogenesis of AD, particularly through mechanisms involving excessive synaptic pruning, highlights potential targets of therapeutic intervention. However, despite these insights, our understanding of how microglia-neuron interactions are altered under neuroinflammatory conditions, such as those present in AD, remains limited. This gap is largely due to the absence of physiologically relevant in vitro models that faithfully recapitulate the complex cellular and molecular milieu of the human brain. Here, I present a novel microphysiological platform enabling long-term culture of 3D primary cortical microtissues, generated using a custom injection mold to produce scaffold-free, self-assembled tissues. This system allows high-resolution, real-time imaging of neuronal calcium activity and cell-type-specific morphology, integrated with automated tools to analyze synaptic maturation and pruning. Importantly, I show that this platform supports the engraftment of human iPSC-derived microglia (iMG), establishing a xenograft culture model. Engrafted iMG functionally integrate into rodent-derived cortical tissues, exhibiting dynamic surveillance and robust responses to neuroinflammatory stimuli and focal tissue lesions. Using AD-relevant microtissues derived from rats carrying human APP and PS1 mutations, I observed extracellular Aβ aggregation, microglial activation, and aberrant synaptic pruning, leading to synaptic loss and neuronal dysfunction. Early glial reactivity and excessive synapse elimination disrupted network maturation, mirroring key features of AD pathology. This versatile platform recapitulates key neuroimmune interactions and offers a powerful tool for dissecting mechanisms of microglia-mediated synaptic dysfunction and for testing therapeutic interventions across neurodevelopmental and neurodegenerative disorders.
- Notes:
- Thesis (Ph. D.)--Brown University, 2025
Citation
Brown, Sophie Corinne,
"Engineering a 3D cortical culture model to investigate spatiotemporal dynamics of microglia-neuron interactions in Alzheimer’s disease"
(2025).
Engineering Theses and Dissertations.
Brown Digital Repository. Brown University Library.
https://repository.library.brown.edu/studio/item/bdr:2d7wahcr/
