Fig 1: Tau seeding correlates with oligomeric 3R and 4R tau levels.a Schematic diagram of the epitopes of tau antibodies used for western blot analysis. b, c Representative western blots of ITG b and PFC c lysates from twenty AD cases (subject no. 1–5, 11–15, 6–10, 16–20) developed with total tau (Tau13), anti-3R and 4 R tau antibodies. d, e Immunoblots were densitometrically quantified, normalized by total protein and HMW-3R and 4 R tau levels in the ITG d and PFC e were correlated with seeding. Two-tailed Spearman’s rank non-parametric correlation tests were used, and r coefficient and P values are indicated on the tables. f Correlation of the ratio of 3R-tau/4R-tau in the ITG from twenty AD cases with seeding is shown. A two-tailed Spearman’s rank non-parametric correlation test was used, and r coefficient and P values are indicated on the plot. g, h Quantification of HMW and LMW-total tau and isoform levels in the ITG of low and high seeders, represented as fold change of low seeders. Data are presented as mean ± SEM; n = 6 AD cases per group. *P < 0.05, **P < 0.01, ***P < 0.001 (t test). (i) Relative 3 R/4 R HMW-tau ratio in the ITG from six low and six high seeders was detected by immunoblots. Results represent the mean ± SEM; ***P < 0.001 (t test).
Fig 2: Tau seeding bioactivity correlates with cognitive decline in AD.a Graphs showing dementia progression in patients from Banner Sun Health Research Institute (cohort 1) and Mount Sinai ADRC (cohort 2). A line corresponds to a single patient and each dot to a visit at the research clinic. The patients were evaluated for their MMSE (cohort 1) or CDR-SOB (cohort 2) scores at each visit. b Schematic representation of the in vitro FRET-based tau seeding assay. c Representative 40× confocal images of FRET-biosensor cells showing no seeding, low and high tau seeding after treatment with a control and AD soluble brain lysates, with FRET-positive tau inclusions shown in bright green and nuclear DAPI staining in blue. Scale bar, 20 µm. d, e Graphs representing tau seeding activity (% FRET-positive cells) induced by ITG d and PFC e. Brain lysates from one cognitively unimpaired control and twenty patients were used. f, g Tau seeding induced specifically by ITG lysates f were significantly correlated with the rate of cognitive decline in both cohorts while the correlation between seeding by PFC lysates and cognitive decline was not significant g, determined using a two-tailed Spearman’s rank non-parametric test, P and r values are indicated on each plot.
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