Microglia are the primary resident immune cells of the central nervous system that are responsible for the maintenance of brain homeostasis. There is a plethora of evidence to suggest that microglia display distinct phenotypes that are associated with the alteration of cell morphology under varying environmental cues. However, it has not been fully explored how the varying states of microglial activation are linked to the alteration of microglia morphology, especially in the microdomain. The objective of this study was to quantitatively characterize the ultrastructural morphology of human microglia under neuro-inflammatory cues. To address this, a human cell line of microglia was stimulated by anti-inflammatory (IL-4), pro-inflammatory (TNF-α), and Alzheimer's disease (AD)-associated cues (Aβ, Aβ + TNF-α). The resulting effects on microglia morphology associated with changes in microdomain were analyzed using a high-resolution scanning electron microscopy. Our findings demonstrated that microglial activation under pro-inflammatory and AD-cues were closely linked to changes not only in cell shape, but also in cell surface topography and higher-order branching of processes. Furthermore, our results revealed that microglia under pro-inflammatory cues exhibited unique morphological features involving cell-to-cell contact and the formation of vesicle-like structures. Our study provides insight into the fine details of microglia morphology associated with varying status of microglial activation.

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