Fig 2: MC1 staining reveals aggregated human tau in Tau mice lacking PS1 and both PS. Immunohistochemical images (left) and quantitative analysis (right) of MC1 stained sections in 6 month-old control (WT), Tau, PS1 cKO;Tau and PS cKO;Tau mice. Scale bar: 100 μm. Values represent mean of MC1-positive cells/section ± s.e.m. (n = 3 slices per mouse, 4 mice/group). Statistical analysis was determined by one-way ANOVA followed by Tukey’s post hoc tests. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. Abbreviations: Amygdala: basolateral amygdala; CA1/CA3 hippocampus; EC, entorhinal cortex ,

Fig 3: Effect of single and multiple exposure of gamma irradiation on phosphorylation of JNK, ERK and Tau proteins. Brain homogenates from various experimental mice were studied to identify the phosphorylation of stress related proteins such as JNK, ERK and Tau. Representative western blot and densitometric analysis of (A) pJNK normalized using total JNK (Wt; n = 5, Tg; n = 5 per group) (B) pERK normalized using total ERK (Wt; n = 5, Tg; n = 5 per group) and (C) pTau (ser 199) normalized using β-actin (Wt; n = 5, Tg; n = 5 per group). Different groups are indicated as Wt (Wild type), Tg (Untreated Transgenic), Tg+0.5 (S) (Transgenic mice received single dose of 0.5 Gy radiation), Tg+0.5 (M) (Transgenic mice received 0.5 Gy radiation twice a week for one month), Tg+4 (S) (Transgenic mice received single dose of 4 Gy radiation). Values are expressed as mean ± SEM. ∗p < 0.05 compared to wild type and #p < 0.05 compared to untreated APP/PS1 mice (Tg).

Fig 4: Increased pathological PKA-mediated tau phosphorylation in Tau mice lacking PS. Left: Representative immunohistochemical images of phosphorylated tau (PG5: pSer409) in 6 month-old non- and tau transgenic mice. Inset: magnified images showing somatic PG5 staining in PS cKO;Tau brains. Scale bar: 100 μm. Right: Quantitative analysis of number of PG5-positive cells/section in the indicated brain region in littermate control (WT), Tau, PS1 cKO;Tau and PS cKO;Tau mice. Values represent mean PG5-positive cells ± s.e.m. (3 slices per mouse, 4–5 mice/group). Statistical analysis was determined by two-way ANOVA followed by Tukey’s post hoc tests. *P < 0.05, **P < 0.01, ***P < 0.001. Abbreviations: Amygdala: basolateral amygdala; CA1/CA3 hippocampus; DG, dentate gyrus; EC, entorhinal cortex; RSC, retrosplenial cortex

Fig 5: Reduced synaptic proteins and accumulation of synaptic tau in PS-deficient Tau mice. Western blot images (top) and quantification (bottom) of synaptic proteins and phosphorylated Ser202 (CP13) and total (D1M9X) tau in hippocampal lysates (left) and purified postsynaptic fractions (right) of WT, Tau, PS1 cKO;Tau and PS cKO;Tau mice at 6 months. # indicates a young 3 month-old PS cKO;Tau mouse. Protein levels were normalized to β-tubulin in the lysates and total loaded protein (1 μg) in postsynaptic fractions. D1M9X antibody was used for reblotting after CP13 membrane stripping. Notice the lack of typical presynaptic proteins (syntaxin 1A, synaptophysin, β-tubulin) in the postsynaptic fractions. Values represent mean fold ± s.e.m. (n = 3 mice/group). Statistical analysis was determined by one-way ANOVA followed by Tukey’s post hoc tests. *P < 0.05