Fig. 6: Genetic Cyp46a1 overexpression in microglia significantly ameliorates neurological deficit post stroke. | Nature Metabolism

Fig. 6: Genetic Cyp46a1 overexpression in microglia significantly ameliorates neurological deficit post stroke.

From: Cholesterol metabolic reprogramming mediates microglia-induced chronic neuroinflammation and hinders neurorestoration following stroke

Fig. 6

a, Schematic diagram illustrating the strategy used to generate microglia-specific Cyp46a1 overexpression in adult male mice. b, Experimental timeline for testing the effects of microglial Cyp46a1 overexpression during the chronic stage post MCAO. TEM, transmission electron microscopy. c,d, Motor and balance functions were assessed using the rotarod test (c) and foot-fault test (d) in MCAO mice with or without Cyp46a1 overexpression. Cyp46a1-conditional knock-in (cKI), n = 16 mice; control, n = 13 mice. e,f, Cognitive function was evaluated using the Y-maze test (day 72 post MCAO) (e) and NOR test (day 70 post MCAO) (f). Cyp46a1-cKI, n = 16 mice; control, n = 13 mice. g,h, T2-weighted MRI (g) and quantification (h) showing reduced brain lesion volume in mice with Cyp46a1 overexpression. Cyp46a1-cKI, n = 16 mice; control, n = 13 mice. i,j, MBP immunostaining (i) and quantification (j) indicate improved white matter integrity in Cyp46a1-overexpressing mice. Cyp46a1-cKI, n = 12 mice; control, n = 10 mice. k, Representative transmission electron microscopy images of the basal ganglia on day 74 post MCAO. Red arrowheads indicate demyelinated axons. l, The G-ratio (ratio of the inner axon diameter to the total outer fibre diameter) was compared between Cyp46a1-cKI and control mice. Cyp46a1-cKI, n = 105 axons from three mice; control, n = 98 axons from three mice. m,n, Lipid droplet (LD) visualization (m) and quantification (n) in microglia from the lesion area of Cyp46a1-cKI or control MCAO mice. Cyp46a1-cKI, n = 12 mice; control, n = 10 mice. o, Microglia-specific Cyp46a1 overexpression suppressed pro-inflammatory gene expression in microglia post MCAO. Cyp46a1-cKI, n = 3 mice; control, n = 4 mice. Colour legend in n applies to all bar graphs. Data are presented mean and s.d. Statistical significance was assessed by two-way ANOVA (c,d) followed by Bonferroni’s multiple comparisons test or two-tailed unpaired Student’s t-test (e,f,h,j,l,n).

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