Fig 2: CSS results in lasting increases in soluble tau protein in the LC and EC. A, Comparison of MC1 and oligomer (TOMA-1) tau immunoblots from same LC purified protein samples from a Rest P301S mouse (R) and a CSS P301S mouse (C) run under reducing (Red) conditions (left) and nonreducing (NRed) conditions (right). B, Representative NRed LC gels (20 μg/lane) from Rest, CSS, and Tau−/− mice for antibodies to phosphoserine 202 (P202), phosphothreonine 231 (AT180), MC1 tau (MC1), and total tau (Tau5). C, Representative NRed gels from EC in Rest, CSS, and Tau−/− mice for the same antibodies. D–G, Individual normalized immunodensities at 50–80 kDa (monomeric) for LC lysates to P202, AT180, MC1, and Tau5. Individual data points: blue represents male; pink represents female. n = 9 (5 male, 4 female) for the LC samples. Error bars indicate mean ± SE. H–K, Individual normalized immunodensities at 50–80 kDa for EC for the same antibodies and conditions where n = 14 (9 male, 5 female) for the EC samples. L–O, Individual normalized immunodensities at 90–160 kDa for LC lysates to the same tau antibodies/conditions from the same gels analyzed for monomeric LC. P–S, Individual normalized immunodensities at 90–160 kDa for EC lysates and antibodies, analyzed on gels used for monomeric analysis. Data were analyzed with unpaired t tests. *p < 0.05, **p < 0.01, ***p < 0.001.

Fig 3: Model of antibody engagement of tau in-vivo.A compartmental model depicting tau and antibody (IgG) levels in brain, interstitial fluid (ISF), cerebrospinal fluid (CSF) and plasma. CSF tau is truncated with levels of ~1 nM, while tau in ISF exists as a full-length molecule with levels of 3–5 nM (4-5x greater than in CSF) [47]. Concentrations of p-tau are estimated to be about 1–10% of total tau levels. Tau antibody concentrations are 1–3 nM in CSF and ISF [44]. Antibody engagement of p-tau in CSF and ISF would enable clearance of tau via a variety of antibody-mediated mechanisms. Full-length tau is indicated as a molecule containing N-terminal (orange line), mid-domain (blue line), microtubule-binding repeat region (black box), and C-terminal (grey line) regions, whereas truncated tau in the CSF compartment is indicated by the mid-domain and N-terminal fragments.

Fig 4: Special stains and tau immunohistochemistry for neurofibrillary tangle (NFT) maturity levels. Representative images for each staining technique were taken at the CA1 sector of the hippocampus in Alzheimer's disease (AD) brains. Routine and special stains include Bielschowsky silver stain, H&E, Congo red, thioflavin‐S (Thio‐S), and thiazin red. All routine and special stains recognized mature tangles and ghost tangles. For immunohistochemistry, Alz‐50, MC‐1, CP13, AT8, PHF‐1, pS396, TauC3, GT‐38, Ab39, and MN423 were used. Tau antibodies recognized a range of NFT maturity levels. Immunohistochemistry was counterstained with hematoxylin. We thank Dr. García‐Sierra for the thiazin red image. Arrow head, pretangles; closed arrow, mature tangles; open arrow, ghost tangles. Scale bar measures 25 μm.

Fig 5: Impaired gamma oscillations in more advanced stages of tauopathy(A) Normalized power spectra (right panel) were produced by subtracting the aperiodic component (left panel, gray line) from the power spectrum.(B) Average normalized spectrum during rest, focusing on the frequency ranges in which gamma peaks were observed during presentation of gray screen (top) and stimulus (bottom). Amplitude of stimulus-induced gamma was smaller in 8-month Tau+ animals (F(2,59) = 3.822; p = 3 × 10−6). Gray rectangles indicate approximate 6 Hz windows used to calculate mean normalized power in D.(C) There was no difference in the center frequency of detected gamma-rhythm, during presentation of gray screen or stimulus.(D) Mean normalized power for a 6 Hz range around the mean center frequencies for the relevant gamma peaks. Tau+ mice showed smaller mean power for stimulus-induced gamma at 8 months (WT x Tau+, p = 0.004; Tau-x Tau+, p = 0.032), but not at 5 months, or during gray screen periods (F(2,59) = 0.870, p = 0.589). Shaded area in B represents ±1 s.e.m from the mean (line). Data in C and D are represented as mean ±1 s.e.m using opaque symbols, and transparent symbols show individual animals. All comparisons were performed using a two-way ANOVA. Statistical comparisons in black highlight comparisons between Tau- and Tau + animals, while statistical comparisons in gray are for comparisons of any Tau group and WT littermates. ∗p < 0.05; ∗∗p < 0.01.