Fig. 1.

TYROBP deficiency rapidly increases phosphorylated tau levels in a MAPT^P301S transgenic mouse model of tauopathy. a MAPT^P301S mice were crossed with Tyrobp^-/- mice, yielding progeny with genotypes of: (1) MAPT^P301S mice expressing wild-type TYROBP (abbreviated MAPT^P301S); (2) MAPT^P301S mice heterozygous for Tyrobp knock-out (abbreviated MAPT^P301S;Tyrobp^+/-); (3) MAPT^P301S mice homozygous for Tyrobp knock-out (abbreviated MAPT^P301S;Tyrobp^-/-). Male and female mice (2 months of age) were used for this experiment. b Representative western blots of tissues from mice of the indicated genotype were performed using antibodies as indicated: antibody AT8 (detects paired helical filament epitopes of tau phosphorylated at residues serine 202 and/or threonine 205); antibody anti-tau (phospho S³⁹⁶) (detects tau phosphorylated at residue serine 396); antibody T46 (detects total tau); anti-GAPDH. Extracts from cortex, hippocampus and spinal cord from male and female mice of the indicated genotypes were studied. Full-length blots are presented in Supplementary Figure 2. c Densitometric analyses of western blots standardized to total tau or GAPDH. n = 7 (MAPT^P301S), n = 11 (MAPT^P301S;Tyrobp^+/-) or n = 7 (MAPT^P301S;Tyrobp^-/-) for extracts from cortex; n = 8 (MAPT^P301S), n = 9 (MAPT^P301S;Tyrobp^+/-) or n = 8 (MAPT^P301S;Tyrobp^-/-) for extracts from hippocampus; n = 8 (MAPT^P301S), n = 11 (MAPT^P301S;Tyrobp^+/-) or n = 7 (MAPT^P301S;Tyrobp^-/-) for extracts from spinal cord. Material from male and female mice was pooled for analysis. d Representative images of immunohistochemistry with antibody AT8. Hemibrain scale bar = 1 mm; high magnification scale bar = 200 μm. Error bars represent means ± SEM. Statistical analyses were performed using one-way ANOVA followed by Tukey’s post-hoc test, *p < 0.05; **p < 0.01; ***p < 0.001