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, 17 (4), e12790

Glucocorticoid-mediated Modulation of Morphological Changes Associated With Aging in Microglia

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Glucocorticoid-mediated Modulation of Morphological Changes Associated With Aging in Microglia

Lynn van Olst et al. Aging Cell.

Abstract

Microglia dynamically adapt their morphology and function during increasing age. However, the mechanisms behind these changes are to date poorly understood. Glucocorticoids (GCs) are long known and utilized for their immunomodulatory actions and endogenous GC levels are described to alter with advancing age. We here tested the hypothesis that age-associated elevations in GC levels implicate microglia function and morphology. Our data indicate a decrease in microglial complexity and a concomitant increase in GC levels during aging. Interestingly, enhancing GC levels in young mice enhanced microglial ramifications, while the knockdown of the glucocorticoid receptor expression in old mice aggravated age-associated microglial amoebification. These data suggest that GCs increase ramification of hippocampal microglia and may modulate age-associated changes in microglial morphology.

Keywords: glucocorticoid receptor; glucocorticoids; hippocampus; inflammaging; microglia; neuroimmunology; neuroinflammation.

Figures

Figure 1
Figure 1
Age‐associated alterations in GC levels inversely correlate with age‐associated decreases in both CD11b+ cell coverage and morphological complexity. (a) Micrographs displaying hippocampal CD11b staining. (b) Hippocampal CD11b surface area percentage bar graph. (c) Blood plasma circadian amplitude [GC] bar graph. (d) Regression curves of plasma [GC] and hippocampal CD11b surface area. (e) Micrographs displaying hippocampal sections’ CD11b (left) and Iba1 (right) immunoreactivity. (f) Micrographs displaying hippocampal sections’ CD11b (white) and Iba1 (red) immunoreactivity. Boxed area (top) is magnified in bottom panels of individual CD11b+ cell morphology (left) and traces (right). (g) Sholl plots displaying CD11b+ cell branch intersections per 5 μm steps from the cell soma. (h) Sholl‐derived area under curve (arbitrary units: A.U.) bar graph. (i) Regression curves of plasma [GC] and hippocampal CD11b+ cell complexity as shown in Sholl‐derived area under curve (A.U.). (j) Single z‐plane confocal micrographs displaying CD11b+ cells with GR+ nuclei (arrowheads). (k) CD11b+/GR+ or GR‐ cell quantification (nd, not detected). (l) Regression curves of plasma [GC] and hippocampal CD11b+ cells/mm3. Significant differences are indicated as follows: **< 0.01, ***< 0.001, vs. 3 months, one‐way ANOVA. Scale bars = 50 (a), 20 (e,f), and 16 (j) μm.
Figure 2
Figure 2
GC‐mediated modulation of hippocampal CD11b+ cell morphology in 3‐month‐old mice and GR‐mediated modulation of hippocampal CD11b+ cell morphology in 20‐month‐old mice. (a) Experimental setup used for panels b–f. (b) Micrographs displaying hippocampal CD11b (white) and Iba1 (red) staining after GC treatment on low magnification (top left) and separate immunoreactivity of CD11b and Iba1 (top right). CD11b staining in boxed area of the top left panel is magnified (bottom left panels) to show individual cells and their respective tracings (bottom right panels). (c) AM and PM blood plasma GC levels bar graph and significant differences are indicated as follows: ***< 0.001, AM vs. PM in vehicle, ns > 0.05, AM vs. PM in GC and GC + recovery; #< 0.001, CORT AM and PM vs. vehicle AM and PM; §< 0.001, both AM and PM in vehicle and GC vs. GC + recovery. (d) Hippocampal CD11b surface area bar graph. (e) Sholl plots displaying CD11b+ cell intersections per 5 μm steps from the cell soma. (f) Sholl analysis‐derived area under curve (arbitrary units: A.U.). (d–f) Significant differences are indicated as follows: *< 0.05, ***< 0.001, vs. vehicle, one‐way ANOVA. (g) Experimental setup used for panels h‐n. (h) Micrographs displaying GR intensity in CD11b+ (top panels) and Iba1+ (bottom panels) cells of siSCR (left)‐ and siGR (right)‐injected hippocampi. Boxed areas are shown as separate channels below. (i) CD11b+ (top) and Iba1+ (bottom) cell nuclear GR intensity quantifications for siSCR and siGR treatments. (j) Micrographs displaying CD11b staining of siSCR (left)‐ and siGR (right)‐treated hippocampi. (k) Hippocampal CD11b surface area quantification. (l) Micrographs displaying individual CD11b+ cell morphology (left) and traces (right) of siSCR (top)‐ and siGR (bottom)‐treated hippocampi. (m) Sholl plots displaying CD11b+ cell branch complexity per 1 μm steps from the cell soma. (n) Sholl analysis‐derived area under curve quantifications of siSCR‐ and siGR‐treated mice (arbitrary units: A.U.) (i, k, and n) Significant differences are indicated as follows: *< 0.05, ***< 0.001, siSCR vs. siGR, Student's t test. Scale bars = 20 (b), 10 (h), and 7 μm (j and l).

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