Amyloid Plaques and Normal Ageing Have Differential Effects on Microglial Ca Activity in the Mouse Brain

In microglia, changes in intracellular calcium concentration ([Ca]) may regulate process motility, inflammasome activation, and phagocytosis. However, while neurons and astrocytes exhibit frequent spontaneous Ca activity, microglial Ca signals are much rarer and poorly understood. Here, we studied [Ca] changes of microglia in acute brain slices using Fluo-4-loaded cells and mice expressing GCaMP5g in microglia. Spontaneous Ca transients occurred ~ 5 times more frequently in individual microglial processes than in their somata. We assessed whether microglial Ca responses change in Alzheimer's disease (AD) using App knock-in mice. Proximity to Aβ plaques strongly affected microglial Ca activity. Although spontaneous Ca 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 responses, partly resembling those of wild-type microglia. By contrast, somatic Ca 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 signals. Finally, as similar processes occur in neurodegeneration and old age, we studied whether ageing affected microglial [Ca]. Somatic damage-evoked Ca 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 signals in microglial somata but reduced the rate of events in processes. Thus, we demonstrate distinct compartmentalised Ca activity in microglia from healthy, aged and AD-like brains.