Amyloidosis and ageing have differential effects on microglial Ca ²⁺ activity in the mouse brain

In microglia, changes in intracellular calcium concentration ([Ca ²⁺ ] _i ) may regulate process motility, inflammasome activation, and phagocytosis. However, while neurons and astrocytes exhibit frequent spontaneous Ca ²⁺ activity, microglial Ca ²⁺ signals are much rarer and poorly understood. Here, we studied [Ca ²⁺ ] _i changes of microglia in acute brain slices using Fluo-4–loaded cells and mice expressing GCaMP5g in microglia. Spontaneous Ca ²⁺ transients occurred ∼5 times more frequently in individual microglial processes than in their somata. We assessed whether microglial Ca ²⁺ responses change in Alzheimer’s disease (AD) using App ^{NL- G-F} knock-in mice. Proximity to Aβ plaques strongly affected microglial Ca ²⁺ activity. Although spontaneous Ca ²⁺ transients were unaffected in microglial processes, they were 5-fold more frequent in microglial somata near Aβ plaques than in wild-type microglia. Microglia away from Aβ plaques in AD mice showed intermediate properties for morphology and Ca ²⁺ responses, partly resembling those of wild-type microglia. By contrast, somatic Ca ²⁺ responses evoked by tissue damage were less intense in microglia near Aβ plaques than in wild-type microglia, suggesting different mechanisms underlying spontaneous vs. damage-evoked Ca ²⁺ signals. Finally, as similar processes occur in neurodegeneration and old age, we studied whether ageing affected microglial [Ca ²⁺ ] _i . Somatic damage-evoked Ca ²⁺ responses were greatly reduced in microglia from old mice, as in the AD mice. In contrast to AD, however, old age did not alter the occurrence of spontaneous Ca ²⁺ signals in microglial somata but reduced the rate of events in processes. Thus, we demonstrate distinct compartmentalised Ca ²⁺ activity in microglia from healthy, aged and AD-like brains.