Amyloid plaques and normal ageing have differential effects on microglial Ca2+ activity in the mouse brain

In 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+](i) changes of microglia in acute brain slices using Fluo-4-loaded cells and mice expressing GCaMP5g in microglia. Spontaneous Ca2+ transients occurred similar to 5 times more frequently in individual microglial processes than in their somata. We assessed whether microglial Ca2+ responses change in Alzheimer's disease (AD) using App(NL-G-F) knock-in mice. Proximity to A beta plaques strongly affected microglial Ca2+ activity. Although spontaneous Ca2+ transients were unaffected in microglial processes, they were fivefold more frequent in microglial somata near A beta plaques than in wild-type microglia. Microglia away from A beta 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 A beta 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.

Automated summary

Changes in intracellular calcium levels in microglia can affect their motility, activation, and phagocytosis. However, the understanding of microglial calcium signals is limited. This study found that spontaneous calcium transients occur more frequently in microglial processes than in their somata. Proximity to A beta plaques in Alzheimer's disease strongly impacts microglial calcium activity. Aging reduces the occurrence of spontaneous calcium signals but does not affect the frequency of these signals in microglial somata. The findings suggest distinct compartmentalized calcium activity in microglia from healthy, aged, and Alzheimer's-like brains.