Abstract
Brain aging is characterized by a chronic, low-grade inflammatory state, promoting deficits in cognition and the development of age-related neurodegenerative diseases. Malfunction of microglia, the brain-resident immune cells, was suggested to play a critical role in neuroinflammation, but the mechanisms underlying this malfunctional phenotype remain unclear. Specifically, the age-related changes in microglial Ca2+ signaling, known to be linked to its executive functions, are not well understood. Here, using in vivo two-photon imaging, we characterize intracellular Ca2+ signaling and process extension of cortical microglia in young adult (2–4-month-old), middle-aged (9–11-month-old), and old (18–21-month-old) mice. Our data revealed a complex and nonlinear dependency of the properties of intracellular Ca2+ signals on an animal’s age. While the fraction of cells displaying spontaneous Ca2+ transients progressively increased with age, the frequencies and durations of the spontaneous Ca2+ transients followed a bell-shaped relationship, with the most frequent and largest Ca2+ transients seen in middle-aged mice. Moreover, in old mice microglial processes extending toward an ATP source moved faster but in a more disorganized manner, compared to young adult mice. Altogether, these findings identify two distinct phenotypes of aging microglia: a reactive phenotype, abundantly present in middle-aged animals, and a dysfunctional/senescent phenotype ubiquitous in old mice.
Highlights
Microglia are the brain-resident macrophages of the central nervous system (CNS) and, as such, they provide the first line of immune defense in response to injury or disease
The fraction of spontaneously active cells was significantly higher in old mice compared to young adult mice (p = 0.02 for 2–4- vs. 18–21-month-old mice, p = 0.25 for 2–4- vs. 9–11-month-old mice and p > 0.99 for 9–11- vs. 18–21-month-old mice, Kruskal–Wallis test; n = 9, 5, and 8 mice for 2–4, 9–11, and 18–21-month-old mice, respectively). (D) Cumulative probability distributions of frequency of spontaneous Ca2+ transients in 2–4, 9–11, and 18–21- month-old mice. (E) Box-and-whisker plot illustrating the frequency of Ca2+ transients in spontaneously active cells of the three age groups
Our results obtained in old mice (~50% of microglial cells displaying spontaneous Ca2+ signaling) complete the picture and identify the aging-related microglial hyperactivity as a new hallmark of the aging brain
Summary
Microglia are the brain-resident macrophages of the central nervous system (CNS) and, as such, they provide the first line of immune defense in response to injury or disease. Microglia account for 5–12% of the total number of cells in the mouse brain [1] and 0.5–16.6% in the human brain, depending on the region studied [2]. Upon infection or tissue damage, microglia recognize pathogen-associated molecular patterns (PAMPs) present on the surface of intruders and/or damage-associated molecular patterns (DAMPs) released by injured or stressed cells [14], triggering neuroinflammatory responses to help the system to restore its homeostatic balance. Depending on the exact nature of the stimuli, microglia increase the production of pro- and/or anti-inflammatory cytokines, chemokines, reactive oxygen species (ROS), as well as enhance the phagocytic, migratory and proliferative activity [4,14]. The known limitation of inferring function from morphology in microglia is that their functional state is not always reflected by morphological changes [17,18]
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