Fig. 1: Heparan sulfate proteoglycan (HSPG)-dependent internalization of soluble extracellular tau aggregates by brain microvascular endothelial cells triggers endogenous tau phosphorylation (Thr231). | Nature Communications

Fig. 1: Heparan sulfate proteoglycan (HSPG)-dependent internalization of soluble extracellular tau aggregates by brain microvascular endothelial cells triggers endogenous tau phosphorylation (Thr231).

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

Fig. 1

A–C Soluble aggregated tau internalization triggers endogenous tau phosphorylation in primary human brain microvascular endothelial cells (HBEC). A Soluble tau aggregates accumulate in brain microvasculature of P301S(PS19) mice. Representative images of cortical brain sections from 8-month-old male and female P301S(PS19) and WT controls showing soluble tau aggregates (T22, green) and total tau (Tau5, cyan) immunoreactivity in lectin-stained microvasculature (red). Nine independent samples (three brain sections from each of three mice) were examined over three independent experiments. B Representative images of primary HBEC exposed to soluble aggregates of V5-tagged recombinant human tau-441 or vehicle (control) in the presence or absence of heparin, immunostained with antibodies for V5 (green) and α/β-tubulin (red), and counterstained with DAPI (blue). Scale bar is 200 µm. Nine independent samples were examined over 3 independent experiments. C Representative electropherograms from capillary electrophoresis immunoassays for phosphorylated tau (T231) and β-actin in lysates from HBEC treated with recombinant human cytokeratin-8 (KRT8), monomeric tau protein (M. Tau), unlabeled soluble tau aggregates (O.Tau), or vehicle (control). D Quantitative analyses of data in C (F(3,22) = 3.115, ANOVA, p = 0.047. Control vs. O. Tau, *, P < 0.05. Control, n = 12; KRT8, n = 4; M. Tau, n = 4, O. Tau, n = 6 biologically independent samples examined over 6 independent experiments. Data are means ± SEM. E, F Atomic force microscopy profiling of tau. E Representative AFM images of field fragments with soluble tau aggregates, tagged (V5) and untagged. F Size distribution of tau particles as measured by AFM show overlapping distributions of soluble tau aggregates (>12 nm in length) in non-tagged and V5-tagged soluble tau aggregate preparations (Soluble tau aggregates V5, n = 405 particles; soluble tau aggregates, n = 403 particles [i.e., biologically independent samples (particles measured) examined over 1 independent experiment]. Data are frequency profiles. For post-hoc analyses, lack of a specific P value in the legend reflects the information reported by GraphPad Prism Version 9.4.0.

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