Fig. 6: GD1a exhibits superior avidity for tau aggregates compared to GM1.
From: Ganglioside sialylation modulates tau internalization and pathology spread
a GD1a and recombinant tau151-391 protein were incubated and subjected to pull-down assay utilizing rabbit anti-Tau antibodies,with rabbit IgG (rIgG) as a control. The input samples and precipitates are analyzed by dot blot using mouse anti-GD1a and anti-Tau (HT7) antibodies. b SPR assay characterizing the interaction between GD1a and tau151-391. GD1a concentrations used were 7.8 μM, 15.6 μM, 31.2 μM, 62.5 μM, 125 μM, and 250 μM (arranged from bottom to top). Inset, SPR data were fitted to a 1:1 Langmuir binding model. c SPR analysis characterizing the specific binding of GM1 to tau151-391, with GM1 concentrations of 15.6 μM, 31.2 μM, 62.5 μM, 125 μM, 250 μM, and 500 μM (arranged from bottom to top). Colour lines, SPR data from varying analyte concentrations. Black lines, data were fitted to a steady-state model. d Equal amounts of monomeric tau151-391 (M-tau) and fibrillated tau151-391 (F-tau) were incubated with GM1 and then subjected to a pull-down assay using mouse (m) anti-tau antibody HT7. e The levels of input and pulled-down GM1 (normalized to tau) from d were calculated and analyzed using Student’s t test (n = 3). Input, P = 0.9373; IP, P = 0.6277. f Equal amounts of M-tau and F-tau were incubated with GD1a and then subjected to a pull-down assay using rabbit (r) anti-tau antibodies. g The levels of input and pulled-down GD1a (normalized to tau) from f was calculated and analyzed using Welch’s t test (n = 3). Input, P = 0.7718. h F-tau were incubated with GM1 or GD1a, followed by centrifugation. The resulting pellets were subjected to dot blots. i The levels of GM1 and GD1a from h was measured. j Docking interactions between AD PHF tau (purple) and sialic acid (blue) are depicted. Contacting residues are presented in stick representation (green). Yellow dashed lines, hydrogen bonds. k Left panels, GD1a on the cell membrane mediates the adhesion of AD P-tau via additional sialic acid, facilitates AD P-tau internalization through LRP1 and contributes to the spread of tau pathology. Right panels, Overexpression of Neu3, which removes one sialic acid from GD1a, or the administration of GM1 both decrease the GD1a/GM1 ratio at the cell membrane. This change reduces the local concentration of AD P-tau recruited by GD1a, thereby decreasing the uptake of AD P-tau by LRP1. This inhibition of tau pathology transmission results in a protective effect against cognitive impairment related to AD P-tau.
