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Reprogramming astrocytic NDRG2/NF-κB/C3 signaling restores the diabetes-associated cognitive dysfunction

Jiang, Tao, Li, Yansong, He, Shuxuan, Huang, Ning, Du, Mengyu, Zhai, Qian, Pu, Kairui, Wu, Meiyan, Yan, Chaoying, Ma, Zhi, Wang, Qiang·2023·eBioMedicine
DOI 10.1016/j.ebiom.2023.104653PMC PMC10300300
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Fig. 1 Transcriptomic analysis revealed the protective effect of exercise and the integrative pathogenesis of DACD. (a) Schematic that represents the chronological order of STZ injection, exercise, cognitive testing, and omics analysis. (b) The alternation triplet (%) of Y-maze was decreased in STZ group compared with vehicle mice (∗p = 0.0145 between vehicle and STZ), which was reversed by exercise (n = 9/group) (∗p = 0.0339 between STZ and STZ + Run). (c) Y-maze total arm entries (n = 9/group). (d) Representative traces of diabetic or non-diabetic mice after exercise in MWM test. (e) Escape latency of the MWM test was delayed in STZ mice compared with vehicle (∗∗p = 0.004 (day 1), ∗∗p = 0.0077 (day 2), ∗∗∗∗p < 0.0001 (day 3), ∗∗∗∗p < 0.0001 (day 4), ∗∗p = 0.0028 (day 5) between vehicle and STZ), which was rescued after exercise (n = 10 vehicle and v + Run, n = 9 STZ and STZ + Run) (#p = 0.0282 (day 1), ##p = 0.001 (day 2), #p = 0.0154 (day 3), #p = 0.0151 (day 4), #p = 0.0391 (day 5) between STZ and STZ + Run). (f–g) The platform crossover (f) and target quadrant retention time (%) (g) during the probe trial of the MWM test were decreased in STZ mice compared with the vehicle group (∗∗p = 0.0016 (f), ∗p = 0.0158 (g) between vehicle and STZ), which were upregulated after exercise (n = 10 vehicle and v + Run, n = 9 STZ and STZ + Run) (∗p = 0.0444 (f), ∗p = 0.0359 (g) between STZ and STZ + Run). (h) Cluster dendrogram of WGCNA in transcriptome showing the 18 modules, distinguished by different colors (n = 5/group). (i) PCA analysis of transcriptomic samples. (j) Multidimensional distribution of 18 modules by PCA analysis. (k) Correlation network demonstrating the major cell types and Gene Ontology enrichments for each module and the relationships from a multidimensional perspective. Yellow represents a positive correlation, and grey represents a negative correlation. (l) The module eigengene of module 1 was downregulated at diabetic mice (∗∗∗∗p < 0.0001 between vehicle and STZ), which was reversed by exercise (n = 5/group) (∗∗∗∗p < 0.0001 between STZ and STZ + Run). (m) Module 1 enriched neuronal synaptic plasticity genes: Syt 1, Manf, Syp, and Bdnf. Values are presented as mean ± SEM. One-way ANOVA with Tukey's multiple comparisons test was performed in b, f, g, l. Two-way ANOVA with Tukey's multiple comparisons test was performed in e.
Fig. 1 Transcriptomic analysis revealed the protective effect of exercise and the integrative pathogenesis of DACD. (a) Schematic that represents the chronological order of STZ injection, exercise, cognitive testing, and omics analysis. (b) The alternation triplet (%) of Y-maze was decreased in STZ group compared with vehicle mice (∗p = 0.0145 between vehicle and STZ), which was reversed by exercise (n = 9/group) (∗p = 0.0339 between STZ and STZ + Run). (c) Y-maze total arm entries (n = 9/group). (d) Representative traces of diabetic or non-diabetic mice after exercise in MWM test. (e) Escape latency of the MWM test was delayed in STZ mice compared with vehicle (∗∗p = 0.004 (day 1), ∗∗p = 0.0077 (day 2), ∗∗∗∗p < 0.0001 (day 3), ∗∗∗∗p < 0.0001 (day 4), ∗∗p = 0.0028 (day 5) between vehicle and STZ), which was rescued after exercise (n = 10 vehicle and v + Run, n = 9 STZ and STZ + Run) (#p = 0.0282 (day 1), ##p = 0.001 (day 2), #p = 0.0154 (day 3), #p = 0.0151 (day 4), #p = 0.0391 (day 5) between STZ and STZ + Run). (f–g) The platform crossover (f) and target quadrant retention time (%) (g) during the probe trial of the MWM test were decreased in STZ mice compared with the vehicle group (∗∗p = 0.0016 (f), ∗p = 0.0158 (g) between vehicle and STZ), which were upregulated after exercise (n = 10 vehicle and v + Run, n = 9 STZ and STZ + Run) (∗p = 0.0444 (f), ∗p = 0.0359 (g) between STZ and STZ + Run). (h) Cluster dendrogram of WGCNA in transcriptome showing the 18 modules, distinguished by different colors (n = 5/group). (i) PCA analysis of transcriptomic samples. (j) Multidimensional distribution of 18 modules by PCA analysis. (k) Correlation network demonstrating the major cell types and Gene Ontology enrichments for each module and the relationships from a multidimensional perspective. Yellow represents a positive correlation, and grey represents a negative correlation. (l) The module eigengene of module 1 was downregulated at diabetic mice (∗∗∗∗p < 0.0001 between vehicle and STZ), which was reversed by exercise (n = 5/group) (∗∗∗∗p < 0.0001 between STZ and STZ + Run). (m) Module 1 enriched neuronal synaptic plasticity genes: Syt 1, Manf, Syp, and Bdnf. Values are presented as mean ± SEM. One-way ANOVA with Tukey's multiple comparisons test was performed in b, f, g, l. Two-way ANOVA with Tukey's multiple comparisons test was performed in e.CC BY-NC-ND · PubMed Central
Fig. 2 Exercise promotes neuronal morphology and function in diabetic mice. (a) Representative images of neuronal dendritic morphology. Scale bar, 75 μm. (b–c) Quantification of dendritic complexity (b) and total dendritic length (c) by Sholl analysis exhibited a decline in the STZ group compared with vehicle mice (∗p = 0.0192 between vehicle and STZ), which was increased after exercise (n = 15/group) (∗p = 0.0297 between STZ and STZ + Run). (d–f) The densities of total spines (d), stubby spines (e), and mushroom spines (f) were downregulated in the STZ group compared with vehicle mice (∗∗∗∗p < 0.0001 (d), ∗∗p = 0.0078 (e), ∗∗∗∗p < 0.0001 (f) between vehicle and STZ), which all rescued after exercise (n = 20/group) (∗∗∗p = 0.0003 (d), ∗∗p = 0.0078 (e), ∗∗p = 0.0026 (f) between STZ and STZ + Run). (g) Representative images of dendritic spine 3D reconstruction to classify stubby, mushroom, long thin, and filopodia spines. Scale bar, 5 μm. (h–i) Representative immunoblots of synaptic proteins: PSD95 (h) and SYP (i) (n = 6/group) (∗p = 0.0118 (h), ∗p = 0.0291 (i) between vehicle and STZ) (∗p = 0.0209 (h), ∗p = 0.0345 (i) between STZ and STZ + Run). (j) Representative images of mEPSC traces in CA1 pyramidal neurons. (k, m) Average neuron mEPSC frequency (k) and amplitude (m) (n = 9/group) (∗∗∗p = 0.0002 between vehicle and STZ, ∗p = 0.0159 between STZ and STZ + Run). (l, n) Cumulative distributions of mEPSC frequency (l) and amplitude (n) (n = 9/group). Data are presented as mean ± SEM. One-way ANOVA with Tukey's multiple comparisons test was performed in c–f, h–i, k.
Fig. 2 Exercise promotes neuronal morphology and function in diabetic mice. (a) Representative images of neuronal dendritic morphology. Scale bar, 75 μm. (b–c) Quantification of dendritic complexity (b) and total dendritic length (c) by Sholl analysis exhibited a decline in the STZ group compared with vehicle mice (∗p = 0.0192 between vehicle and STZ), which was increased after exercise (n = 15/group) (∗p = 0.0297 between STZ and STZ + Run). (d–f) The densities of total spines (d), stubby spines (e), and mushroom spines (f) were downregulated in the STZ group compared with vehicle mice (∗∗∗∗p < 0.0001 (d), ∗∗p = 0.0078 (e), ∗∗∗∗p < 0.0001 (f) between vehicle and STZ), which all rescued after exercise (n = 20/group) (∗∗∗p = 0.0003 (d), ∗∗p = 0.0078 (e), ∗∗p = 0.0026 (f) between STZ and STZ + Run). (g) Representative images of dendritic spine 3D reconstruction to classify stubby, mushroom, long thin, and filopodia spines. Scale bar, 5 μm. (h–i) Representative immunoblots of synaptic proteins: PSD95 (h) and SYP (i) (n = 6/group) (∗p = 0.0118 (h), ∗p = 0.0291 (i) between vehicle and STZ) (∗p = 0.0209 (h), ∗p = 0.0345 (i) between STZ and STZ + Run). (j) Representative images of mEPSC traces in CA1 pyramidal neurons. (k, m) Average neuron mEPSC frequency (k) and amplitude (m) (n = 9/group) (∗∗∗p = 0.0002 between vehicle and STZ, ∗p = 0.0159 between STZ and STZ + Run). (l, n) Cumulative distributions of mEPSC frequency (l) and amplitude (n) (n = 9/group). Data are presented as mean ± SEM. One-way ANOVA with Tukey's multiple comparisons test was performed in c–f, h–i, k.CC BY-NC-ND · PubMed Central
Fig. 3 Exercise reverses the downregulation of astrocytic NDRG2 in the diabetic hippocampus. (a) Astrocytic and oligodendrocytic genes (Ndrg2, Lcn2, and Mobp) were enriched in module 2. (b–c) Representative immunofluorescent staining of NDRG2 in the hippocampus (b); the fluorescent intensity (c) was decreased at STZ group compared with vehicle mice (∗∗∗∗p < 0.0001 between vehicle and STZ), which was upregulated by exercise (∗∗∗∗p < 0.0001 between STZ and STZ + Run). Red: NDRG2, green: GFAP, purple: NeuN. Scale bar, 25 μm. (d–e) Representative immunoblots of astrocytic NDRG2 in the hippocampus exhibited downregulated at STZ mice compared with vehicle (∗∗∗∗p < 0.0001 between vehicle and STZ), which was increased after exercise (n = 6/group) (∗∗p = 0.0018 between STZ and STZ + Run). Data are presented as mean ± SEM. One-way ANOVA with Tukey's multiple comparisons test was performed in c, e.
Fig. 3 Exercise reverses the downregulation of astrocytic NDRG2 in the diabetic hippocampus. (a) Astrocytic and oligodendrocytic genes (Ndrg2, Lcn2, and Mobp) were enriched in module 2. (b–c) Representative immunofluorescent staining of NDRG2 in the hippocampus (b); the fluorescent intensity (c) was decreased at STZ group compared with vehicle mice (∗∗∗∗p < 0.0001 between vehicle and STZ), which was upregulated by exercise (∗∗∗∗p < 0.0001 between STZ and STZ + Run). Red: NDRG2, green: GFAP, purple: NeuN. Scale bar, 25 μm. (d–e) Representative immunoblots of astrocytic NDRG2 in the hippocampus exhibited downregulated at STZ mice compared with vehicle (∗∗∗∗p < 0.0001 between vehicle and STZ), which was increased after exercise (n = 6/group) (∗∗p = 0.0018 between STZ and STZ + Run). Data are presented as mean ± SEM. One-way ANOVA with Tukey's multiple comparisons test was performed in c, e.CC BY-NC-ND · PubMed Central
Fig. 4 NDRG2 deficiency reverses the beneficial effect of exercise on the dendritic spine and cognitive function in diabetic mice. (a) Schematic representing chronological order of STZ injection, exercise, AAV-Cre to induce NDRG2 deficiency, and behavioral testing. (b) Representative microscopic fields of NDRG2 deficiency in the hippocampus. Red: NDRG2, green: GFP/GFAP, blue: DAPI. Scale bar, 40 μm. (c) The escape latency of MWM tests. (d–e) The platform crossover (d) and target quadrant retention time (%) (e) of MWM tests were decreased in the STZ + Run + acNDRG2 KO group (n = 5) compared with STZ + Run + control mice (n = 6) (∗p = 0.0208 (d), ∗p = 0.0477 (e) between STZ + Run + acNDRG2 KO and STZ + Run + control). (f) Representative images of dendritic spine 3D reconstruction in the STZ + Run + acNDRG2 KO and STZ + Run + control mice. Scale bar, 5 μm. (g–j) The densities of total spines (g), stubby spines (h), mushroom spines (i), and long thin spines (j) were downregulated in the STZ + Run + acNDRG2 KO group compared with STZ + Run + control mice (n = 20/group) (∗∗∗∗p < 0.0001 (g), ∗p = 0.0164 (h), ∗∗p = 0.0035 (i), ∗p = 0.0153 (j) between STZ + Run + acNDRG2 KO and STZ + Run + control). (k) The densities of filopodia spines (n = 20/group). Data are presented as mean ± SEM. Two-tailed Student's t-test was performed in d–j.
Fig. 4 NDRG2 deficiency reverses the beneficial effect of exercise on the dendritic spine and cognitive function in diabetic mice. (a) Schematic representing chronological order of STZ injection, exercise, AAV-Cre to induce NDRG2 deficiency, and behavioral testing. (b) Representative microscopic fields of NDRG2 deficiency in the hippocampus. Red: NDRG2, green: GFP/GFAP, blue: DAPI. Scale bar, 40 μm. (c) The escape latency of MWM tests. (d–e) The platform crossover (d) and target quadrant retention time (%) (e) of MWM tests were decreased in the STZ + Run + acNDRG2 KO group (n = 5) compared with STZ + Run + control mice (n = 6) (∗p = 0.0208 (d), ∗p = 0.0477 (e) between STZ + Run + acNDRG2 KO and STZ + Run + control). (f) Representative images of dendritic spine 3D reconstruction in the STZ + Run + acNDRG2 KO and STZ + Run + control mice. Scale bar, 5 μm. (g–j) The densities of total spines (g), stubby spines (h), mushroom spines (i), and long thin spines (j) were downregulated in the STZ + Run + acNDRG2 KO group compared with STZ + Run + control mice (n = 20/group) (∗∗∗∗p < 0.0001 (g), ∗p = 0.0164 (h), ∗∗p = 0.0035 (i), ∗p = 0.0153 (j) between STZ + Run + acNDRG2 KO and STZ + Run + control). (k) The densities of filopodia spines (n = 20/group). Data are presented as mean ± SEM. Two-tailed Student's t-test was performed in d–j.CC BY-NC-ND · PubMed Central
Fig. 5 NDRG2 overexpression alleviates synaptic injury and memory deficits at diabetic mice. (a) Schematic representing chronological order of STZ injection, NDRG2 overexpression, and behavioral testing. (b) Representative immunofluorescent staining of NDRG2 overexpression in the hippocampus. Red: NDRG2, green: GFAP, purple: NeuN, blue: DAPI. Scale bar, 100 μm. (c) Y-maze alternation triplet (%) were increased at the STZ + AAV-NDRG2 group compared to STZ + AAV-Ctrl group (n = 8/group) (∗∗p = 0.0082 between vehicle + AAV-Ctrl and STZ + AAV-Ctrl) (∗p = 0.0368 between STZ + AAV-NDRG2 and STZ + AAV-Ctrl). (d–e) Y-maze total arm entries (d) and total distance (e) (n = 8/group). (f) Representative traces of diabetic or non-diabetic mice after NDRG2 overexpression from the MWM test. (g) Escape latency was reduced at the STZ + AAV-NDRG2 mice compared to STZ + AAV-Ctrl group (n = 8/group) (∗p = 0.0279 (day 3), ∗p = 0.0456 (day 4), ∗∗∗p = 0.0007 (day 5) between vehicle + AAV-Ctrl and STZ + AAV-Ctrl) (#p = 0.0341 (day 2), #p = 0.0297 (day 4), ##p = 0.0100 (day 5) between STZ + AAV-NDRG2 and STZ + AAV-Ctrl). (h) Swimming velocity during the MWM test (n = 8/group). (i–j) The platform crossover (i) and target quadrant retention time (%) (j) during the probe trial of the MWM test were increased after NDRG2 overexpression (n = 8/group) (∗∗∗p = 0.0005 (i), ∗p = 0.0331(j) between vehicle + AAV-Ctrl and STZ + AAV-Ctrl) (∗∗∗p = 0.0007 (i), ∗∗p = 0.0067 (j) between STZ + AAV-NDRG2 and STZ + AAV-Ctrl). (k–n) Representative immunoblots of synaptic proteins: PSD95 (k, m) and SYP (l, n), the protein levels improved in the STZ + AAV-NDRG2 group compared to STZ + AAV-Ctrl mice (n = 6/group) (∗p = 0.0138 (m), ∗p = 0.010 (n) between vehicle + AAV-Ctrl and STZ + AAV-Ctrl) (∗∗p = 0.0014 (m), ∗∗∗p = 0.0006 (n) between STZ + AAV-NDRG2 and STZ + AAV-Ctrl). (o) Representative images of 3D reconstruction of dendritic spines. Scale bar, 5 μm. (p) The densities of total spines were upregulated at the STZ + AAV-NDRG2 group compared to STZ + AAV-Ctrl mice (n = 20/group) (∗∗∗∗p < 0.0001 between vehicle + AAV-Ctrl and STZ + AAV-Ctrl) (∗∗∗p = 0.0002 between STZ + AAV-NDRG2 and STZ + AAV-Ctrl). Data are presented as mean ± SEM. One-way ANOVA with Tukey's multiple comparisons test was performed in c, i–p. Two-way ANOVA with Tukey's multiple comparisons test was performed in g.
Fig. 5 NDRG2 overexpression alleviates synaptic injury and memory deficits at diabetic mice. (a) Schematic representing chronological order of STZ injection, NDRG2 overexpression, and behavioral testing. (b) Representative immunofluorescent staining of NDRG2 overexpression in the hippocampus. Red: NDRG2, green: GFAP, purple: NeuN, blue: DAPI. Scale bar, 100 μm. (c) Y-maze alternation triplet (%) were increased at the STZ + AAV-NDRG2 group compared to STZ + AAV-Ctrl group (n = 8/group) (∗∗p = 0.0082 between vehicle + AAV-Ctrl and STZ + AAV-Ctrl) (∗p = 0.0368 between STZ + AAV-NDRG2 and STZ + AAV-Ctrl). (d–e) Y-maze total arm entries (d) and total distance (e) (n = 8/group). (f) Representative traces of diabetic or non-diabetic mice after NDRG2 overexpression from the MWM test. (g) Escape latency was reduced at the STZ + AAV-NDRG2 mice compared to STZ + AAV-Ctrl group (n = 8/group) (∗p = 0.0279 (day 3), ∗p = 0.0456 (day 4), ∗∗∗p = 0.0007 (day 5) between vehicle + AAV-Ctrl and STZ + AAV-Ctrl) (#p = 0.0341 (day 2), #p = 0.0297 (day 4), ##p = 0.0100 (day 5) between STZ + AAV-NDRG2 and STZ + AAV-Ctrl). (h) Swimming velocity during the MWM test (n = 8/group). (i–j) The platform crossover (i) and target quadrant retention time (%) (j) during the probe trial of the MWM test were increased after NDRG2 overexpression (n = 8/group) (∗∗∗p = 0.0005 (i), ∗p = 0.0331(j) between vehicle + AAV-Ctrl and STZ + AAV-Ctrl) (∗∗∗p = 0.0007 (i), ∗∗p = 0.0067 (j) between STZ + AAV-NDRG2 and STZ + AAV-Ctrl). (k–n) Representative immunoblots of synaptic proteins: PSD95 (k, m) and SYP (l, n), the protein levels improved in the STZ + AAV-NDRG2 group compared to STZ + AAV-Ctrl mice (n = 6/group) (∗p = 0.0138 (m), ∗p = 0.010 (n) between vehicle + AAV-Ctrl and STZ + AAV-Ctrl) (∗∗p = 0.0014 (m), ∗∗∗p = 0.0006 (n) between STZ + AAV-NDRG2 and STZ + AAV-Ctrl). (o) Representative images of 3D reconstruction of dendritic spines. Scale bar, 5 μm. (p) The densities of total spines were upregulated at the STZ + AAV-NDRG2 group compared to STZ + AAV-Ctrl mice (n = 20/group) (∗∗∗∗p < 0.0001 between vehicle + AAV-Ctrl and STZ + AAV-Ctrl) (∗∗∗p = 0.0002 between STZ + AAV-NDRG2 and STZ + AAV-Ctrl). Data are presented as mean ± SEM. One-way ANOVA with Tukey's multiple comparisons test was performed in c, i–p. Two-way ANOVA with Tukey's multiple comparisons test was performed in g.CC BY-NC-ND · PubMed Central
Fig. 6 NDRG2 reshapes the pathological structure of astrocytes by inhibiting NF-κB/C3 signaling. (a) GSEA of proteome indicated complement and coagulation cascade signaling were upregulated in diabetic mice (∗∗∗p = 0.0002 between vehicle and STZ) and downregulated after exercise (∗∗p = 0.0035 between STZ and STZ + Run). The cumulative enrichment scores were normalized (NES) (n = 3/group). (b) Heatmaps showing the fold changes of significantly altered proteins in complement and coagulation cascades (n = 3/group). (c–d) Representative immunofluorescent staining of intact C3 and its cleaved products in the hippocampus. Red: C3, green: GFAP, blue: DAPI. Scale bar, 50 μm. (∗∗∗p = 0.0006 between vehicle and STZ, ∗∗∗p = 0.0006 between STZ and STZ + Run) (e–f) Representative immunoblots of complement C3 in the hippocampus were increased in the STZ group compared to vehicle mice (∗∗∗∗p < 0.0001 between vehicle and STZ), which was downregulated after exercise (n = 6/group) (∗∗∗p = 0.0008 between STZ and STZ + Run). (g–k) Representative immunoblots of astrocytic NDRG2 (g, i), complement C3 (g, h), NF-κB, and p–NF–κB (j, k) after NDRG2 loss of function (n = 6/group) (∗p = 0.0120 (h), ∗∗∗∗p < 0.0001 (i), ∗∗p = 0.0012 (k) between STZ + Run + acNDRG2 KO and STZ + Run + control). (l–n) Representative immunoblots of astrocytic NDRG2 (l), complement C3 (m), NF-κB, and p–NF–κB (n) in the hippocampus after NDRG2 gain of function (n = 6/group) (∗∗p = 0.0064 (l), ∗∗∗p = 0.0001 (m), ∗∗p = 0.0029 (n) between vehicle + AAV-Ctrl and STZ + AAV-Ctrl) (∗∗∗∗p < 0.0001 (l), ∗p = 0.0264 (m), ∗∗p = 0.0040 (n) between STZ + AAV-NDRG2 and STZ + AAV-Ctrl). Data are presented as mean ± SEM. GSEA analysis was performed in a. One-way ANOVA with Tukey's multiple comparisons test was performed in d, f, l–n. Two-tailed Student's t-test was performed in h, i, k.
Fig. 6 NDRG2 reshapes the pathological structure of astrocytes by inhibiting NF-κB/C3 signaling. (a) GSEA of proteome indicated complement and coagulation cascade signaling were upregulated in diabetic mice (∗∗∗p = 0.0002 between vehicle and STZ) and downregulated after exercise (∗∗p = 0.0035 between STZ and STZ + Run). The cumulative enrichment scores were normalized (NES) (n = 3/group). (b) Heatmaps showing the fold changes of significantly altered proteins in complement and coagulation cascades (n = 3/group). (c–d) Representative immunofluorescent staining of intact C3 and its cleaved products in the hippocampus. Red: C3, green: GFAP, blue: DAPI. Scale bar, 50 μm. (∗∗∗p = 0.0006 between vehicle and STZ, ∗∗∗p = 0.0006 between STZ and STZ + Run) (e–f) Representative immunoblots of complement C3 in the hippocampus were increased in the STZ group compared to vehicle mice (∗∗∗∗p < 0.0001 between vehicle and STZ), which was downregulated after exercise (n = 6/group) (∗∗∗p = 0.0008 between STZ and STZ + Run). (g–k) Representative immunoblots of astrocytic NDRG2 (g, i), complement C3 (g, h), NF-κB, and p–NF–κB (j, k) after NDRG2 loss of function (n = 6/group) (∗p = 0.0120 (h), ∗∗∗∗p < 0.0001 (i), ∗∗p = 0.0012 (k) between STZ + Run + acNDRG2 KO and STZ + Run + control). (l–n) Representative immunoblots of astrocytic NDRG2 (l), complement C3 (m), NF-κB, and p–NF–κB (n) in the hippocampus after NDRG2 gain of function (n = 6/group) (∗∗p = 0.0064 (l), ∗∗∗p = 0.0001 (m), ∗∗p = 0.0029 (n) between vehicle + AAV-Ctrl and STZ + AAV-Ctrl) (∗∗∗∗p < 0.0001 (l), ∗p = 0.0264 (m), ∗∗p = 0.0040 (n) between STZ + AAV-NDRG2 and STZ + AAV-Ctrl). Data are presented as mean ± SEM. GSEA analysis was performed in a. One-way ANOVA with Tukey's multiple comparisons test was performed in d, f, l–n. Two-tailed Student's t-test was performed in h, i, k.CC BY-NC-ND · PubMed Central
Fig. 7 C3aR blockade rescues dendritic spine loss in diabetic mice, and C3 may be a biomarker to predict the progression of DACD in humans. (a) Schematic representing chronological order of STZ injection, C3aR antagonist, and behavioral testing. We used C3aR antagonists to clarify whether C3aR blockade could mimic the protective effect of NDRG2 overexpression on DACD. (b) Y-maze alternation triplet (%) was improved in the STZ + C3aRA group compared with STZ + PBS mice (n = 7/group, n = 8 vehicle + PBS) (∗∗∗p = 0.0006 between vehicle + PBS and STZ + PBS) (∗∗∗∗p < 0.0001 between STZ + C3aRA and STZ + PBS). (c–d) Y-maze total distance (c) and total arm entries (d) (n = 7/group, n = 8 vehicle + PBS). (e) Escape latency of MWM test was shorten at the STZ + C3aRA group compared with STZ + PBS mice (n = 7/group, n = 8 vehicle + PBS) (∗p = 0.0211 (day 1), ∗p = 0.0336 (day 2), ∗∗p = 0.0099 (day 3), ∗∗p = 0.0033 (day 4) between vehicle + PBS and STZ + PBS) (##p = 0.0021 (day 1), #p = 0.0392 (day 3) between STZ + C3aRA and STZ + PBS). (f) Platform crossover of MWM test was upregulated at the STZ + C3aRA mice compared to STZ + PBS group (n = 7/group, n = 8 vehicle + PBS) (∗∗p = 0.0025 between vehicle + PBS and STZ + PBS) (∗∗p = 0.0066 between STZ + C3aRA and STZ + PBS). (g) Representative images of 3D reconstruction of dendritic spines. Scale bar, 5 μm. (h–l) The densities of total spines (h), stubby spines (i), mushroom spines (j), long thin spines (k), and filopodia spines (l) (n = 20/group) (∗∗∗∗p < 0.0001 (h), ∗∗∗p = 0.0008 (i), ∗p = 0.0191 (j), ∗∗∗p = 0.0006 (k) between vehicle + PBS and STZ + PBS) (∗∗∗∗p < 0.0001 (h), ∗∗∗p = 0.0005 (i), ∗p = 0.0133 (j), ∗p = 0.0153 (l) between STZ + C3aRA and STZ + PBS). (m) The DSST scores of diabetic patients (n = 27) and non-diabetic peers (n = 13) (∗∗∗∗p < 0.0001 between Normal and Diabetes). (n) Fasting plasma glucose levels for diabetic patients (n = 27) compared to non-diabetic patients (n = 13) (∗∗∗∗p < 0.0001 between Normal and Diabetes). (o) The serum levels of complement C3 in diabetic patients (n = 27) and normal peers (n = 13) (∗∗p = 0.0072 between Normal and Diabetes). (p) The correlations between DSST score and increased C3 levels in diabetic patients (n = 27) and normal peers (n = 13). Correlations were found using linear regression, with r = −0.3315 and p = 0.0366. Values presented as mean ± SEM. Two-way ANOVA with Tukey's multiple comparisons test was performed in e. One-way ANOVA with Tukey's multiple comparisons test was performed in b, f–l. Two-tailed Student's t-test was performed in m–o.
Fig. 7 C3aR blockade rescues dendritic spine loss in diabetic mice, and C3 may be a biomarker to predict the progression of DACD in humans. (a) Schematic representing chronological order of STZ injection, C3aR antagonist, and behavioral testing. We used C3aR antagonists to clarify whether C3aR blockade could mimic the protective effect of NDRG2 overexpression on DACD. (b) Y-maze alternation triplet (%) was improved in the STZ + C3aRA group compared with STZ + PBS mice (n = 7/group, n = 8 vehicle + PBS) (∗∗∗p = 0.0006 between vehicle + PBS and STZ + PBS) (∗∗∗∗p < 0.0001 between STZ + C3aRA and STZ + PBS). (c–d) Y-maze total distance (c) and total arm entries (d) (n = 7/group, n = 8 vehicle + PBS). (e) Escape latency of MWM test was shorten at the STZ + C3aRA group compared with STZ + PBS mice (n = 7/group, n = 8 vehicle + PBS) (∗p = 0.0211 (day 1), ∗p = 0.0336 (day 2), ∗∗p = 0.0099 (day 3), ∗∗p = 0.0033 (day 4) between vehicle + PBS and STZ + PBS) (##p = 0.0021 (day 1), #p = 0.0392 (day 3) between STZ + C3aRA and STZ + PBS). (f) Platform crossover of MWM test was upregulated at the STZ + C3aRA mice compared to STZ + PBS group (n = 7/group, n = 8 vehicle + PBS) (∗∗p = 0.0025 between vehicle + PBS and STZ + PBS) (∗∗p = 0.0066 between STZ + C3aRA and STZ + PBS). (g) Representative images of 3D reconstruction of dendritic spines. Scale bar, 5 μm. (h–l) The densities of total spines (h), stubby spines (i), mushroom spines (j), long thin spines (k), and filopodia spines (l) (n = 20/group) (∗∗∗∗p < 0.0001 (h), ∗∗∗p = 0.0008 (i), ∗p = 0.0191 (j), ∗∗∗p = 0.0006 (k) between vehicle + PBS and STZ + PBS) (∗∗∗∗p < 0.0001 (h), ∗∗∗p = 0.0005 (i), ∗p = 0.0133 (j), ∗p = 0.0153 (l) between STZ + C3aRA and STZ + PBS). (m) The DSST scores of diabetic patients (n = 27) and non-diabetic peers (n = 13) (∗∗∗∗p < 0.0001 between Normal and Diabetes). (n) Fasting plasma glucose levels for diabetic patients (n = 27) compared to non-diabetic patients (n = 13) (∗∗∗∗p < 0.0001 between Normal and Diabetes). (o) The serum levels of complement C3 in diabetic patients (n = 27) and normal peers (n = 13) (∗∗p = 0.0072 between Normal and Diabetes). (p) The correlations between DSST score and increased C3 levels in diabetic patients (n = 27) and normal peers (n = 13). Correlations were found using linear regression, with r = −0.3315 and p = 0.0366. Values presented as mean ± SEM. Two-way ANOVA with Tukey's multiple comparisons test was performed in e. One-way ANOVA with Tukey's multiple comparisons test was performed in b, f–l. Two-tailed Student's t-test was performed in m–o.CC BY-NC-ND · PubMed Central
Graphical Abstract The integrative mechanism of astrocytic NDRG2 and complement cascades in regulating neuronal synaptic plasticity. Overexpression of astrocytic NDRG2 inhibited over-activation of complement cascades mediated by C3 protein, thus alleviating cognitive dysfunction in diabetic mice. NDRG2 acts as a regulator of astrocytic-neuronal interaction via NF-κB/C3/C3aR signaling to restore synaptic function in diabetic mice.
Graphical Abstract The integrative mechanism of astrocytic NDRG2 and complement cascades in regulating neuronal synaptic plasticity. Overexpression of astrocytic NDRG2 inhibited over-activation of complement cascades mediated by C3 protein, thus alleviating cognitive dysfunction in diabetic mice. NDRG2 acts as a regulator of astrocytic-neuronal interaction via NF-κB/C3/C3aR signaling to restore synaptic function in diabetic mice.CC BY-NC-ND · PubMed Central

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Metadata

Authors
Jiang, T., Li, Y., He, S., Huang, N., Du, M., Zhai, Q., Pu, K., Wu, M., Yan, C., Ma, Z., & Wang, Q.
ORCID
Wang, Qiang
Venue
eBioMedicine
Publisher
Elsevier BV
Published
2023-07
Volume
93
Pages
104653
ISSN
2352-3964
DOI
10.1016/j.ebiom.2023.104653
PMC
PMC10300300
Cited by
57
References
14
Language
en
Licence
Funders
  • National Natural Science Foundation of China (81801899, 81971290, 81974540)
  • Fundamental Research Funds for the Central Universities (xzy022019020)
  • Key Research and Development Projects of Shaanxi Province (2022ZDLSF02-09)

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