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. 2012 Jul;26(5):754-65.
doi: 10.1016/j.bbi.2011.11.006. Epub 2011 Dec 2.

Age related changes in microglial phenotype vary between CNS regions: grey versus white matter differences

Adam D Hart  1 , Andreas Wyttenbach, V Hugh Perry, Jessica L Teeling
Affiliations

Age related changes in microglial phenotype vary between CNS regions: grey versus white matter differences

Adam D Hart et al. Brain Behav Immun. 2012 Jul.

Abstract

Subtle regional differences in microglial phenotype exist in the adult mouse brain. We investigated whether these differences were amplified during ageing and following systemic challenge with lipopolysaccharide (LPS). We studied microglial morphology and phenotype in young (4mo) and aged (21mo) C57/BL6 mice using immunohistochemistry and quantified the expression levels of surface molecules on microglia in white and grey matter along the rostral-caudal neuraxis. We detected significant regional, age dependent differences in microglial phenotypes, with the microglia of white matter and caudal areas of the CNS exhibiting greater upregulation of CD11b, CD68, CD11c, F4/80 and FcγRI than grey matter and rostral CNS areas. Upregulation of CD11c with age was restricted to the white matter, as was the appearance of multinucleated giant cells. Systemic LPS caused a subtle upregulation of FcγRI after 24 h, but the other markers examined were not affected. Burrowing behaviour and static rod assays were used to assess hippocampal and cerebellar integrity. Aged mice exhibited exaggerated and prolonged burrowing deficits following systemic LPS injection, while in the absence of an inflammatory challenge aged mice performed significantly worse than young mice in the static rod test. Taken together, these findings show that the effects of age on microglial phenotype and functional integrity vary significantly between CNS compartments, as do, albeit to a lesser extent, the effects of systemic LPS.

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Figures

Supplementary Fig. 1
Supplementary Fig. 1
Supplementary Fig. 2
Supplementary Fig. 2
Fig. 1
Fig. 1
CD11b and CD68 marker expression increases with age and LPS. (A–H) CD11b. (A–D) Hippocampus. A – 4 month old saline, B – 4 month old LPS, C – 21 month old saline, D – 21 month old LPS. (E–G) Cerebellum. E – 4 month old saline, F – 4 month old LPS, G – 21 month old saline, H – 21 month old LPS. (I–P) CD68. (I–L) Hippocampus. I – 4 month old saline, J – 4 month old LPS, K – 21 month old saline, L – 21 month old LPS. (M–P) Cerebellum. M – 4 month old saline, N – 4 month old LPS, O – 21 month old saline, P – 21 month old LPS.
Fig. 2
Fig. 2
Microglial membrane marker expression increases with age. (A, B) Double immunofluorescence staining for CD11b (green) and collagen IV (red) in the fimbria (A) and cerebellar inferior peduncle (B) of a 21 month old mouse. CD11b positive cell aggregates are indicated by white arrows. The aggregates contain multiple nuclei and are not situated directly adjacent to blood vessels, as indicated by collagen IV positive basement membranes. Nuclei are blue after DAPI staining. (C) Double immunofluorescence staining for CD11c (green) and Ki67 (red), a marker of proliferation, in the cerebellar inferior peduncle. CD11c positive aggregates do not co-localise with Ki67 positive nuclei. D&G – CD11c staining in the cerebellar inferior peduncle of a 21 month old (D) and 4 month old (G) mouse. E&H – FcγRI staining in the cerebellar inferior peduncle of a 21 month old (E) and 4 month old (H) mouse. F&I – F4/80 staining in the cerebellar inferior peduncle of a 21 month old (F) and 4 month old (I) mouse.
Fig. 3
Fig. 3
Age related changes in microglial phenotype depends on brain region. Tissue collected and analysed 24 h after intraperitoneal injection of saline or LPS. (A) CD11b expression in selected regions of the CNS. CD11b expression was significantly influenced by age, region and age × region (p < 0.05), but not LPS. n = 4–5 per region. (B) CD68 expression in selected regions of the CNS. CD68 expression was significantly influenced by age, region and age × region, but not LPS (p < 0.001). n = 4–5 per region. (C) F4/80 expression in selected regions of the CNS. F4/80 expression was significantly influenced by age, region and age × region (p < 0.001), but not LPS. n = 4–5 per region. Horizontal bars denote a significant effect of age (4 m saline to 21 m saline) or LPS (21 m saline to 21 m LPS) within that region. Data is shown as mean ± SEM. ∗ denotes p < 0.05; ∗∗ denotes p < 0.01; ∗∗∗ denotes p < 0.001.
Fig. 4
Fig. 4
Age related changes in CD11c and FcγRI expression depends on brain region. Tissue collected and analysed 24 h after intraperitoneal injection of saline or LPS. (A) CD11c expression in selected regions of the CNS. CD11c expression was significantly influenced by age, region and age × region (p < 0.001), but not LPS. n = 5 per region. (B) FcγRI expression in selected regions of the CNS. FcγRI expression was significantly influenced by region, age and LPS (p < 0.05). n = 4–5 mice per region. Horizontal bars denote a significant effect of age (4 m saline to 21 m saline) or LPS (21 m saline to 21 m LPS) within that region. Data is shown as mean ± SEM. ∗ denotes p < 0.05; ∗∗ denotes p < 0.01; ∗∗∗ denotes p < 0.001.
Fig. 5
Fig. 5
Behavioural changes in young and aged mice and the effect of systemic inflammation. (A) Burrowing measured between 3 and 5 h after intraperitoneal injection of LPS (100 μg/kg) or saline. Data shows systemic LPS induced a greater decline in 21 month old mice compared to 4 month old mice. Horizontal bars represent medians. (B) Overnight burrowing after intraperitoneal injection of LPS or saline. Data shows that recovery of burrowing is slower in 21 month old mice compared to 4 month old mice. Horizontal bars represent means. (C) Percentage fail rate in the 9 mm static rod test measured at baseline or between 1 and 2 h after intraperitoneal LPS or saline injection. 21 month old mice failed more frequently in the 9 mm static rod test than 4 months old. This change in performance was independent of strength (Supplementary Fig. 2). Pass/fail ratios were not influenced by injection of saline (open bars) or LPS (black, filled bars). Columns represent the percentage of mice which fail the task. As this graph is representation of binomial data drawn from a single experiment, no error bars are presented. (D) 9 mm static rod transit time to reach platform at baseline. Transit times reflect a decline in performance with age. Data is shown as mean ± SEM. ∗∗∗p < 0.001. Letters denote a significant difference between groups (p < 0.05).
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