Fig. 3: Simvastatin treatment attenuates systemic and neuro-inflammation in aged ApoE-/- mice. | npj Aging and Mechanisms of Disease

Fig. 3: Simvastatin treatment attenuates systemic and neuro-inflammation in aged ApoE-/- mice.

From: Simvastatin therapy attenuates memory deficits that associate with brain monocyte infiltration in chronic hypercholesterolemia

Fig. 3

a 12-months-old ApoE-/- mice (associated with chronic hypercholesterolemia, increased BP, augmented systemic and neuro-inflammation, and memory deficits) were subjected to 8 weeks of cholesterol-lowering therapy (i.e., simvastatin), BP-lowering therapy (i.e., hydralazine), or a combination of both. BP was assessed longitudinally to monitor the effect of the different treatment regimens. Memory function was assessed at 14 months of age. At termination, plasma cholesterol levels were determined by ELISA and systemic and neuro-inflammation were assessed by ELISA, qPCR, WB, and immunofluorescence to characterize the effects of the different treatment regimens on the different signatures we identified to be altered in this model (i.e., plasma cholesterol, BP, inflammatory status and memory function). Schematic created with BioRender. b Effect of cholesterol- and BP-lowering treatment (hydralazine—green circle, simvastatin—pink circles, combination—orange circles) on plasma levels of pro-inflammatory IL12/23 and c IL17 determined by ELISA (N = 10 per group and N = 8 for aged + combination treatment; some samples failed to return a signal and were excluded from analysis). d Effect of cholesterol- and BP-lowering treatment on CD68 mRNA expression in whole brain extracts of aged ApoE-/-mice (N = 5 per group). e Effect of cholesterol- and BP-lowering treatment on the number of CD68 + Iba-1+ cells in the CA1 region of the hippocampus of aged ApoE-/- mice (N = 3 for young and aged + combination treatment; N = 4 for aged control and simvastatin treatment; N = 5 for hydralazine treatment; the two hemispheres were counted separately. f Effect of cholesterol- and BP-lowering treatment on the CD68 + Iba-1+ cells in the DG region of the hippocampus of aged ApoE-/- mice (N = 3 for young and aged + combination treatment; N = 4 for aged control and simvastatin treatment; N = 5 for hydralazine treatment; the two hemispheres were counted separately). g Effect of cholesterol- and BP-lowering treatment on the total Iba-1+ cell count in the CA1 region of the hippocampus of aged ApoE-/- mice (N = 3 for young and aged + combination treatment; N = 4 for aged control and simvastatin treatment; N = 5 for hydralazine treatment; the two hemispheres were counted separately except for one sample in the “aged + hydralazine” group where one hippocampus region was not analyzable). h Effect of cholesterol- and BP-lowering treatment on CD86 mRNA expression in the hippocampus of aged ApoE-/- mice (N = 5 per group). i Effect of cholesterol- and BP-lowering treatment on CD3 protein expression in whole brain lysates of aged ApoE-/- mice (N = 4 for hydralazine- and combination-treated groups and N = 5 for control and simvastatin-treated groups). CD3 was not detected in brain tissue of young ApoE mice. Inset showing representative protein expression pattern. ApoE apolipoprotein E, BP blood pressure, CA cornu ammonis, DG dentate gyrus, Iba-1 ionized calcium-binding adapter molecule-1, IL interleukin, WB Western blotting. Data expressed as mean ± SEM. N denotes number of independent biological replicates. In b–d and f–i, * denotes P ≤ 0.05 relative to young control, & denotes P ≤ 0.05 relative to aged control after one-way ANOVA followed by Tukey’s post hoc testing. In e, * denotes P ≤ 0.05 relative to young control, & denotes P ≤ 0.05 relative to aged control after Kruskal–Wallis followed by Dunn’s post hoc testing.

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