Fig. 4

Small molecule compounds inhibit pTau neuropathology in primary neurons from TgF344-AD transgenic rats. a Schematic of drug efficacy experiments using primary neurons from the TgF344-AD transgenic rat model of AD. One week after cell isolation from day P1 pups, cells were exposed to 100 nM Aβ42 and 1 nM apoE4 and were treated concurrently with 1 μM compound in a final concentration of 0.5% (v/v) DMSO. The cell medium was changed every 3 days by removing half and replacing it with a fresh medium containing Aβ42, apoE4, and compound such that starting concentrations were maintained for the duration of the experiment. At 14 dpe, cells were fixed for ICC. b Representative ICC images of neurons at 14 dpe, treated with compounds at 1 μM, and labeled for Aβ (red), total tau (green), pTau [S202/T205] (white), and cell nuclei (blue). Scale bars = 50 μm. c Percent positive area of Aβ⁺ pathology, relative to the DMSO control group. d Percent positive area of total tau⁺ fluorescence signal, normalized to the total area of Hoechst⁺ fluorescence signal, and relative to the DMSO control group. e Percent positive area of pTau [S202/T205]⁺ pathology, normalized to the total area of Hoechst⁺ fluorescence signal, and relative to the DMSO control group. f Total area of Hoechst⁺ cell nuclei at 14 dpe, relative to the DMSO control group. c–f The data represent the mean ± SD of n = 4 wells per group. *P < 0.05, **P < 0.01, and ***P < 0.001 compared to the DMSO control by one-way ANOVA. g Eight hit compounds were tested for disaggregation of pre-formed heparin-induced tau fibrils. The experiment was replicated twice, and the results were combined. The data represent the mean ± SD of n = 6 wells per group. *P < 0.05, **P < 0.01, and ***P < 0.001 compared to the DMSO control by one-way ANOVA