Fig. 2: Widespread and pronounced early-onset lysosomal activation of microglia is a key feature of Hexb-mediated pathology.

a, Latency to fall in the rotarod assay for Hexb^−/− (n = 15), Hexb^+/− (n = 15) and Hexb^+/+ (n = 15) mice. b, Kaplan–Meier survival curve of Hexb^−/− (n = 15), Hexb^+/− (n = 15) and Hexb^+/+ (n = 15) animals. c, Immunohistochemical pictures of sagittal brain sections from P120 Hexb^−/− and Hexb^+/− mice showing IBA1⁺ microglia (brown). Microglial density (colour-based) and APP⁺ deposits (black dots) are indicated (n = 4 per group). d, Top, immunofluorescence images of IBA1⁺ microglia (red), highlighting CD68⁺ lysosomes (green) from the thalamus at P120. Bottom, 3D reconstruction of IBA1⁺ microglia (red) and CD68⁺ lysosomes (green). e, Quantitative analysis of microglial morphologies. At least three cells per mouse were measured. f, Quantification of IBA1⁺ microglia in the thalamus over disease course. g, Representative immunohistochemical pictures of Mac-3⁺ microglia from the thalamus at P120 (left) and quantification thereof (right). At least 500 cells per mouse were measured. h, Immunohistochemical images from the thalamus at P120 (left) and quantification (right) of GFAP⁺ astrocytes. At least 300 cells per mouse were measured. i, Typical immunohistochemical pictures from the thalamus at P120 (left) and quantification (right) of APP⁺ deposits in the thalamus. At least 300 deposits per mouse were measured. nd, not detected. Data are shown as mean ± s.e.m. Statistical analyses: one-way analysis of variance (ANOVA) with Tukey’s post hoc test (a); log-rank test (b); two-tailed Student’s t-test (e); two-way ANOVA with Sidak’s test (f–i); each symbol in e–i represents an individual mouse. The colour code represents the genotype (orange, Hexb^−/−; blue, Hexb^+/−). Scale bars, 1 mm (c (main images)), 25 μm (c (magnified images),d,g,h,i).

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