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Aging and disease    2016, Vol. 7 Issue (4) : 450-465     DOI: 10.14336/AD.2015.1123
Original Article |
Deletion of Nuclear Factor kappa B p50 Subunit Decreases Inflammatory Response and Mildly Protects Neurons from Transient Forebrain Ischemia-induced Damage
Rolova Taisia1, Dhungana Hiramani1, Korhonen Paula1, Valonen Piia1, Kolosowska Natalia1, Konttinen Henna1, Kanninen Katja1, Tanila Heikki1,2, Malm Tarja1, Koistinaho Jari1,*
1Department of Neurobiology, A.I. Virtanen Institute, University of Eastern Finland
2Department of Neurology, Kuopio University Hospital, Kuopio, Finland
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Transient forebrain ischemia induces delayed death of the hippocampal pyramidal neurons, particularly in the CA2 and medial CA1 area. Early pharmacological inhibition of inflammatory response can ameliorate neuronal death, but it also inhibits processes leading to tissue regeneration. Therefore, research efforts are now directed to modulation of post-ischemic inflammation, with the aim to promote beneficial effects of inflammation and limit adverse effects. Transcription factor NF-κB plays a key role in the inflammation and cell survival/apoptosis pathways. In the brain, NF-κB is predominantly found in the form of a heterodimer of p65 (RelA) and p50 subunit, where p65 has a transactivation domain while p50 is chiefly involved in DNA binding. In this study, we subjected middle-aged Nfkb1 knockout mice (lacking p50 subunit) and wild-type controls of both sexs to 17 min of transient forebrain ischemia and assessed mouse performance in a panel of behavioral tests after two weeks of post-operative recovery. We found that ischemia failed to induce clear memory and motor deficits, but affected spontaneous locomotion in genotype- and sex-specific way. We also show that both the lack of the NF-κB p50 subunit and female sex independently protected CA2 hippocampal neurons from ischemia-induced cell death. Additionally, the NF-κB p50 subunit deficiency significantly reduced ischemia-induced microgliosis, astrogliosis, and neurogenesis. Lower levels of hippocampal microgliosis significantly correlated with faster spatial learning. We conclude that NF-κB regulates the outcome of transient forebrain ischemia in middle-aged subjects in a sex-specific way, having an impact not only on neuronal death but also specific inflammatory responses and neurogenesis.

Keywords cerebrovascular disease      neuroinflammation      neurogenesis      memory      transgenic mice     
Corresponding Authors: Koistinaho Jari   
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These authors had equal contribution and are designated as co-first authors.

Issue Date: 01 August 2016
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Rolova Taisia
Dhungana Hiramani
Korhonen Paula
Valonen Piia
Kolosowska Natalia
Konttinen Henna
Kanninen Katja
Tanila Heikki
Malm Tarja
Koistinaho Jari
Cite this article:   
Rolova Taisia,Dhungana Hiramani,Korhonen Paula, et al. Deletion of Nuclear Factor kappa B p50 Subunit Decreases Inflammatory Response and Mildly Protects Neurons from Transient Forebrain Ischemia-induced Damage[J]. Aging and disease, 2016, 7(4): 450-465.
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Figure 1.  Experimental setup. Wk, week; MWM, Morris Water Maze (swim task).
Figure 2.  The effect of Nfkb1 gene deficiency on mouse spatial learning and memory as assessed by Morris swim task during the week 4 after the BCCAo. (A-B) The length of a path to the hidden platform was assessed over five test days in female (A) and male mice (B). (C) 15 min memory retention expressed as the mean distance to the center of the previous platform location. The data are shown as mean ± SEM. P values are derived from two-way repeated measures or simple two-way ANOVA; * p < 0.05 in comparison to the Nfkb1-wt animals.
Figure 3.  The effects of Nfkb1 gene deficiency and female sex on activity in the open field test assessed during the week 3 after the BCCAo. Total distance moved (A), time spent in the center of the open field (B), the number of fecal pellets produced (C) and the number of rearings (D) during 10 min of free exploration of the novel arena. P values are derived from three-way ANOVA followed by pairwise comparisons with Bonferroni’s adjustment; # p < 0.05, ### p < 0.001 in comparison to the corresponding sham-operated controls; ** p < 0.01, *** p < 0.001 in comparison to the Nfkb1-wt animals.
Figure 4.  Neuronal loss in the hippocampus was predominantly observed in the CA2 area (A, rectangle) and CA1 area (A, arrow) five weeks after the BCCAo. (A) A representative image of NeuN immunostaining in the hippocampal area of ischemic mouse, scale bar = 500 μm; (C-H), representative higher magnification images of NeuN staining in CA2 area in male (C-E) and female (F-H) ischemic Nfkb1-wt (C, F), ischemic Nfkb1-ko (D, G) and sham Nfkb1-wt (E, H) animals, scale bar = 100 μm. (B) NeuN immunoreactivity in the CA2 area as delineated with a rectangle in images (C-H) and expressed as the percentage of the average value in the wt sham group (females and males normalized separately). P values are derived from three-way ANOVA followed by pairwise comparisons with Bonferroni’s adjustment; * p < 0.05 in comparison to the ischemic Nfkb1-wt animals; # p < 0.05, ## p < 0.01 in comparison to the corresponding sham-treated controls.
Figure 5.  Astrocytosis was evaluated by immunostaining with anti-GFAP antibody five weeks after the BCCAo. Astrocytosis was evaluated by immunostaining with anti-GFAP antibody and was observed predominantly in the CA1, CA2 and dentate gyrus (DG) regions of ischemic hippocampus (A) as compared to sham-operated animals (B), scale bar = 500 μm. GFAP immunoreactivity was evaluated in the whole hippocampal area (C) delineated by solid boundary line in (A) and expressed as the percentage of the whole area of interest. P values are derived from three-way ANOVA followed by pairwise comparisons with Bonferroni’s adjustment; * p < 0.05 in comparison to the Nfkb1-wt animals; # p < 0.05, ## p < 0.01, ### p < 0.001 in comparison to the sham-treated controls. Panel (D-I) representative images of GFAP immunoreactivity in the CA2 area of ischemic Nfkb1-wt and ko animals and wt sham controls, scale bar = 100 μm.
Figure 6.  Microgliosis was evaluated by anti-CD45 immunostaining five weeks after the BCCAo. (A), total CD45 immunoreactivity was evaluated in the whole hippocampal area (as delineated in Figure 5 A) and expressed as the percentage of the area of interest. Panel (B-I), representative images of CD45 immunostaining in the whole hippocampal area (B, C) or only CA2 area in the Nfkb1-wt ischemic mice (B, D, G), Nfkb1-ko ischemic mice (E, H) and Nfkb1-wt sham-operated mice (C, F, I). Scale bar in (B-C) equals 500 μm; scale bar in (D-I) equals 100 μm; DG, dentate gyrus. (J-L), CD45 immunoreactivity in CD45high-expressing cells (J; red) co-localized with Iba1-immunoreactivity (K, L; green). (M), the average number of CD45high small round cells (shown in (K-L)) per section. (N-O), a representative picture of Iba1 staining in the CA2 area of the ischemic hippocampus, scale bar equals 100 μm (N) and quantification of Iba1 immunoreactivity in the whole hippocampal area in male mice (O). P values are derived from three-way ANOVA followed by pairwise comparisons with Bonferroni’s adjustment. *** p < 0.001 in comparison to the Nfkb1-wt animals; # p < 0.05, ## p < 0.01, ### p < 0.001 in comparison to the sham-treated controls.
Figure 7.  Neurogenesis in the dentate gyrus area was evaluated by anti-DCX (doublecortin) immunostaining five weeks after the BCCAo. (A-F) Representative images of DCX immunoreactivity in ischemic animals (A, B, D, E), and sham-treated controls (C, F). (D-F) Higher magnification images of the areas delineated with a rectangle in (A-C). Str. gr., stratum granulare (the granular layer); str. mol., stratum moleculare (the molecular layer); arrowheads show post-mitotic immature neurons. Scale bar in (A-C) equals 200 μm; scale bar in (D-F) equals 80 μm. (G) The average number of DCX-positive cell profiles per section. P values are derived from three-way ANOVA followed by pairwise comparisons with Bonferroni’s adjustment; * p < 0.05 in comparison to the Nfkb1-wt animals, ## p < 0.01 main sex effect. (H, I) Correlations between the average number of DCX+ cells and total CD45 immunoreactivity in the hippocampus (two hippocampi per animal analyzed separately) in female (H) and male animals (I). Spearman’s rho (nonparametric) correlation coefficient R was calculated separately for hippocampi with CD45 immunoreactivity < 9.5% (< 10% in the case of females) shown on the left side of the correlation plot and CD45 immunoreactivity > 9.5% shown on the right.
GenderGenotypeBody weight, gPcommAs per animal
MaleNfkb1-wt34.5 ± 0.61.3 ± 0.2
Nfkb1-ko35.4 ± 0.71.4 ± 0.1
FemaleNfkb1-wt26.1 ± 0.61.5 ± 0.1
Nfkb1-ko23.4 ± 0.3***1.3 ± 0.2
Supplementary table 1  Average body weight and the number of posterior communicating arteries (PcommAs) per animal in the wt and Nfkb1-ko male and female mice. Data are shown as mean ± SEM. P values are derived from Student’s t-test; *** p < 0.001 in comparison to the wt female animals.
GenderGenotypeTreatmentArea of the hippocampus
Medial CA1CA2
MaleNfkb1-wtIschemia88.1 ± 6.0 (p = 0.068)75.4 ± 5.3 (p = 0.003)
Sham100.0 ± 2.3100.0 ± 3.6
Nfkb1-koIschemia91.2 ± 2.7 (p = 0.056)82.5 ± 4.1 (p = 0.014)
Sham103.4 ± 2.9102.1 ± 2.4
FemaleNfkb1-wtIschemia101.2 ± 2.0 (p = 0.692)81.8 ± 4.4 (p = 0.005)
Sham100.0 ± 2.0100.0 ± 3.0
Nfkb1-koIschemia101.2 ± 2.2 (p = 0.391)91.5 ± 3.5 (p = 0.061)
Sham104.2 ± 2.7104.5 ± 2.6
Supplementary table 2  NeuN immunoreactivity in medial CA1 and CA2 areas (delineated in Fig. 3) expressed as the percentage of average immunoreactivity in wt sham animals (females and males normalised separately). Data are shown as mean ± SEM. P values are derived from two-way ANOVA followed by pairwise comparisons with Bonferroni’s adjustment and are shown in brackets.
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