Fig 2: Lowering Synaptogyrin-3 expression reverts working memory defects in Tau P301S mice(A) Experimental design based on the working memory protocol in the Morris water maze by Nakazawa et al. (2003) (see STAR Methods).(B) Representative swim tracks of 6- to 7-month-old wild-type, synaptogyrin-3+/-, Tau P301S, and Tau P301S; synaptogyrin-3+/- mice over four daily swims.(C) Average path length (distance swam to find the platform) per swim (1–4) and genotype. Graphs depict mean ± SEM, and statistical significance was calculated using two-way ANOVA with Tukey’s multiple comparisons test (p values compared with swim 1).(D) Average latency (time needed to find platform) per swim (1–4) and genotype. Graphs depict mean ± SEM, and statistical significance was calculated using two-way ANOVA with Tukey’s multiple comparisons test (p values compared with swim 1).

Fig 3: Image analysis results showing the decrease of FKBP52 expression in neurons with Tau-pS422 deposits in the frontal cortex of patients with different tauopathies. A, C, E) FKBP52 expression (green) is visibly decreased in Tau-pS422 (P422, red) positive neurons of AD Braak VI, familial FTLD-Tau and PSP patients respectively (arrowheads) compared with adjacent neurons devoid of evident Tau-pS422 deposits (arrows). B, D, F) Scatter diagrams of image analysis results showing a significant decrease of FKBP52 expression in Tau-pS422 positive neurons of AD Braak VI, familial FTLD-Tau, and PSP patients respectively. Statistical analysis was performed using Student’s t-test, *p < 0.05, ***p < 0.001,±SEM.

Fig 4: The Effect of PolyI:C on p-tau accumulation in the hippocampus: (A) Immunoblots of hippocampal lysate from PP and NN mice at 3, 6, 9 and 16 months, for p-tau, tau, GFAP, Synaptophysin. ß-Actin was used as housekeeping control. (B,D) Relative quantification of Tau, GFAP and Synaptophysin represented in normalized optical density. (C,E) Percentage of relative changes of these proteins compared to the saline treated controls. Representative immunostaining for (F) p-tau (9 months) and (G) p-tau, Aß1-16 and GFAP at 16 months age group. Insert shows a GFAP positive process with internalized p-tau aggregates. Scale bar in F is 45 µm, G is 20 µm. Values represented as mean ± SEM, n = 4–5 mice per age and treatment. *p < 0.05, **p < 0.005, ***p < 0.0005 #p = 0.07. Statistical significance based on two-way ANOVA with Bonferroni post hoc analysis.

Fig 5: Lowering Synaptogyrin-3 expression preserves synaptic plasticity in Tau P301S mice(A) Top: image of a mouse acute hippocampal slice on the multielectrode array (MEA2100; Multichannel Systems) used for field excitatory post-synaptic potential (fEPSP) recordings. Bottom: schematic diagram indicating stimulation of mossy fibers and recording at CA3 stratum lucidum. Right: an example fEPSP recording from mossy fiber-CA3 synapses showing a dramatic reduction of fEPSP amplitude upon application of group II metabotropic glutamate receptors (mGluRs) agonist DCG-IV, and the full recovery upon washing with artificial cerebrospinal fluid (aCSF).(B) fEPSPs were recorded from mossy fiber-CA3 synapses in 6- to 7-month-old wild-type, synaptogyrin-3+/-, Tau P301S, and Tau P301S; synaptogyrin-3+/- mice. After 30 min of stable baseline recordings, long-term potentiation (LTP) was induced by applying three trains of high-frequency (100 Hz) stimulation, and fEPSPs were recorded for 75 additional minutes. Graph depicts mean ± SEM of the amplitude from each of three consecutive recordings (15 s apart), represented as percentage of baseline average.(C) Average amplitude of the fEPSPs recorded before LTP induction (baseline). Graph depicts mean ± SEM, and statistical significance was calculated using one-way ANOVA with Tukey’s multiple comparisons test (p values compared with wild-type mice).(D) Average amplitude of the fEPSPs recorded after LTP induction and represented as percentage of the average amplitude of the fEPSPs recorded at baseline. Graph depicts mean ± SEM, and statistical significance was calculated using one-way ANOVA with Tukey’s multiple comparisons test (p values compared with wild-type mice).(E) Amplitude of the last three fEPSPs recorded 65 min after LTP induction and represented as percentage of the average amplitude of the fEPSPs recorded at baseline. Graph depicts mean ± SEM, and statistical significance was calculated using one-way ANOVA with Tukey’s multiple comparisons test (p values compared with wild-type mice).