Abstract
ABSTRACTIn microglia, changes in intracellular calcium concentration ([Ca2+]i) may regulate process motility, inflammasome activation, and phagocytosis. However, while neurons and astrocytes exhibit frequent spontaneous Ca2+activity, microglial Ca2+signals are much rarer and poorly understood. Here, we studied [Ca2+]ichanges of microglia in acute brain slices using Fluo-4–loaded cells and mice expressing GCaMP5g in microglia. Spontaneous Ca2+transients occurred ∼5 times more frequently in individual microglial processes than in their somata. We assessed whether microglial Ca2+responses change in Alzheimer’s disease (AD) usingAppNL-G-Fknock-in mice. Proximity to Aβ plaques strongly affected microglial Ca2+activity. Although spontaneous Ca2+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 Ca2+responses, partly resembling those of wild-type microglia. By contrast, somatic Ca2+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 Ca2+signals. Finally, as similar processes occur in neurodegeneration and old age, we studied whether ageing affected microglial [Ca2+]i. Somatic damage-evoked Ca2+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 Ca2+signals in microglial somata but reduced the rate of events in processes. Thus, we demonstrate distinct compartmentalised Ca2+activity in microglia from healthy, aged and AD-like brains.
Publisher
Cold Spring Harbor Laboratory