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Fig. 5 | Molecular Neurodegeneration

Fig. 5

From: Transient IKK2 activation in astrocytes initiates selective non-cell-autonomous neurodegeneration

Fig. 5

Local IKK2-CA-induced Bergmann glia activation drives subsequent Purkinje cell loss. a, b Variable loss of Purkinje cells (calbindin-positive) in areas with astrogliosis-like Bergmann glia activation (increased GFAP staining) in IKK2-CA animals at 20 weeks. Areas without detectable degeneration (“early deg”) showing parallel Bergmann glia processes and degenerated areas (“late deg”) are depicted (a). After IKK2-CA repression by doxycycline from 12 weeks of age severe Purkinje cell loss at 20 weeks is evident in areas with Bergmann glia activation, but not in fields with normal Bergmann glia (b). Inlays: higher magnification of GFAP channel in the molecular layer. DAPI co-staining (blue). Scale bars 50 μm (inlays 20 μm). c, d Quantitative analysis of the spatial correlation of Bergmann glia activation (>8% area GFAP+ in the molecular layer) and Purkinje cell degeneration (<15 Purkinje cells/mm) in individual microscopic fields. Degeneration is almost exclusively found in fields with activated Bergmann glia (c). Bergmann glia activation increases between 12 and 20 weeks in IKK2-CA expressing animals, but is arrested by doxycycline (C/D). Fields with activated Bergmann glia display variable Purkinje cell loss at 20 weeks in animals expressing IKK2-CA, whereas after treatment with doxycycline from 12 to 20 weeks, most fields with activated Bergmann glia show prominent Purkinje cell loss (C/D). Purkinje cell loss progresses between 2 weeks (Dox 12-14w) and 8 weeks (Dox 12-20w) after doxycycline application in fields with Bergmann glia activation. c Bergmann glia activation and Purkinje cell numbers in individual fields. Red numbers: percentage of fields in the specific quadrant. Analysis of 6 fields/animal with n = 4/6/9/7/6 animals for Co/IKK2-CA12w/20w/Dox 12-14w/Dox 12-20w. d Percentage and absolute numbers of fields with activated Bergmann glia (green) and Purkinje cell loss (grey) from Co and IKK2-CA mice at the age of 12, 14 and 20 weeks (12w, Dox 12-14w, 20w) are shown. Numbers represent fields with activated Bergmann glia vs. total fields analysed (left panel) and fields with degenerated Purkinje cells and activated Bergmann glia vs. total fields with activated Bergmann glia (right panel). Transgene inactivation via doxycycline application at the age of 12 weeks (Dox 12-20w) stops the increase in Bergmann glia activation compared to animals at 12 w (left panel), but does not stop Purkinje cell loss (right panel). Statistical analysis: Fisher’s exact test, ns: not significant (p > 0.05); ** p < 0.01; *** p < 0.001

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