Plaque‐dependent morphological and electrophysiological heterogeneity of microglia in an Alzheimer's disease mouse model

Microglia, the central nervous system resident innate immune cells, cluster around Aβ plaques in Alzheimer's disease (AD). The activation phenotype of these plaque‐associated microglial cells, and their differences to microglia distant to Aβ plaques, are incompletely understood. We used novel three‐dimensional cell analysis software to comprehensively analyze the morphological properties of microglia in the TgCRND8 mouse model of AD in spatial relation to Aβ plaques. We found strong morphological changes exclusively in plaque‐associated microglia, whereas plaque‐distant microglia showed only minor changes. In addition, patch‐clamp recordings of microglia in acute cerebral slices of TgCRND8 mice revealed increased K⁺ currents in plaque‐associated but not plaque‐distant microglia. Within the subgroup of plaque‐associated microglia, two different current profiles were detected. One subset of cells displayed only increased inward currents, while a second subset showed both increased inward and outward currents, implicating that the plaque microenvironment differentially impacts microglial ion channel expression. Using pharmacological channel blockers, multiplex single‐cell PCR analysis and RNA fluorescence in situ hybridization, we identified Kir and Kv channel types contributing to the in‐ and outward K⁺ conductance in plaque‐associated microglia. In summary, we have identified a previously unrecognized level of morphological and electrophysiological heterogeneity of microglia in relation to amyloid plaques, suggesting that microglia may display multiple activation states in AD.