Amyloid plaques and normal 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 fivefold 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.