Fig. 5: Soluble aggregated tau induces microtubule instability, increases markers of cellular senescence, and blocks eNOS activation in brain microvasculature in 8-month-old male and female P301S(PS19) mice modeling tauopathy. | Nature Communications

Fig. 5: Soluble aggregated tau induces microtubule instability, increases markers of cellular senescence, and blocks eNOS activation in brain microvasculature in 8-month-old male and female P301S(PS19) mice modeling tauopathy.

From: Soluble pathogenic tau enters brain vascular endothelial cells and drives cellular senescence and brain microvascular dysfunction in a mouse model of tauopathy

Fig. 5

A, B Decreased levels of acetylated tubulin in microvasculature of P301S(PS19) mice. A Representative immunofluorescent images of cortical brain sections from WT control and P301S(PS19) mice stained with DAPI (blue) and lectin (red) and immunostained for acetyl-α-tubulin (green); B Quantitation of acetyl-α-tubulin immunoreactive signal co-localized with lectin-reactive brain microvasculature (Unpaired, two-sided Student’s t-test, t(21) = 2.582, *, p = 0.018. Control, n = 12; PS19, n = 11 mice). C, D Decreased eNOS activation in microvasculature isolated from P301S(PS19) mice. C Representative electropherograms from capillary electrophoresis immunoassays of phospho-eNOS (S1176) and total eNOS in microvasculature purified from brains of WT and P301S(PS19) mice. D Quantitative analyses of phospho-eNOS (S1176) normalized to total eNOS levels in isolated brain vasculature of P301S(PS19) mice (Unpaired, two-sided Student’s t-test, t(6.248)=2.662, *p = 0.036. n = 6 mice per group). E, F Increased inhibition of eNOS in microvasculature isolated from P301S(PS19) mice. E Representative electropherograms from capillary electrophoresis immunoassays of phospho-eNOS (T495) and β-actin in microvasculature isolated from brains of WT control and P301S(PS19) mice. F Quantitative analyses of data in E (Student’s t test with Welch’s correction, t(5.966) = 3.370, *, p = 0.0152, n = 6 mice per group). G, H Increased markers of senescence in microvasculature isolated from P301S(PS19) mice. G mRNA abundance for cell cycle arrest mediators cyclin dependent kinase inhibitor 2 A (Cdkn2a, p16, unpaired, two-sided Student’s t test with Welch’s correction, t(19) = 0.77, p = 0.45. WT control, n = 9; PS19, n = 12), cyclin dependent kinase inhibitor 1 A (Cdkn1a, p21, unpaired, two-sided Student’s t test with Welch’s correction (t(13.3) = 2.794, *, p = 0.015. WT control, n = 8; PS19, n = 13) and tumor protein 53 (Tp53, p53, unpaired, two-sided Student’s t test (t(19) = 0.5973, p = 0.56. WT control, n = 10; PS19, n = 11 mice); H Senescence-associated secretory phenotype components interleukin 6 (IL-6, unpaired two-sided Student’s t test, t(17)=1.023, p = 0.32. WT control, n = 9; PS19, n = 10 mice), interleukin 1β (IL-1β, unpaired, two-sided Student’s t test with Welch’s correction, t(12.87) = 2.497, *p = 0.027. WT control, n = 7; PS19, n = 12 mice), tumor necrosis factor α (TNFα, unpaired, two-sided Student’s t test with Welch’s correction, t(10.46) = 2.309, *, p = 0.043. WT control, n = 8; PS19, n = 10 mice), monocyte chemoattractant protein-1 (MCP-1, unpaired, two-sided Student’s t test with Welch’s correction, t(11.07) = 2.794, *, p = 0.018. WT control, n = 7; PS19, n = 12 mice), and plasminogen-activator inhibitor-1 (PAI-1, unpaired, two-sided Student’s t test with Welch’s correction, t(15.53) = 1.701, p = 0.11. WT control, n = 10; PS19, n = 12 mice), measured with quantitative real-time PCR (qRT-PCR) in isolated brain vasculature of WT and P301S(PS19) mice. Data are representative images and electropherograms, and means ± SEM. For post-hoc analyses, the lack of a specific P value in the legend reflects the information reported by GraphPad Prism Version 9.4.0.

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