Dextran sulphate-induced tau assemblies cause endogenous tau aggregation and propagation in wild-type mice

Accumulation of assembled tau protein in the central nervous system is characteristic of Alzheimer’s disease and several other neurodegenerative diseases, called tauopathies. Recent studies have revealed that propagation of assembled tau is key to understanding the pathological mechanisms of these diseases. Mouse models of tau propagation are established by injecting human-derived tau seeds intracerebrally; nevertheless, these have a limitation in terms of regulation of availability. To date, no study has shown that synthetic assembled tau induce tau propagation in non-transgenic mice. Here we confirm that dextran sulphate, a sulphated glycosaminoglycan, induces the assembly of recombinant tau protein into filaments in vitro. As compared to tau filaments induced by heparin, those induced by dextran sulphate showed higher thioflavin T fluorescence and lower resistance to guanidine hydrochloride, which suggests that the two types of filaments have distinct conformational features. Unlike other synthetic filament seeds, intracerebral injection of dextran sulphate-induced assemblies of recombinant tau caused aggregation of endogenous murine tau in wild-type mice. AT8-positive tau was present at the injection site 1 month after injection, from where it spread to anatomically connected regions. Induced tau assemblies were also stained by anti-tau antibodies AT100, AT180, 12E8, PHF1, anti-pS396 and anti-pS422. They were thioflavin- and Gallyas-Braak silver-positive, indicative of amyloid. In biochemical analyses, accumulated sarkosyl-insoluble and hyperphosphorylated tau was observed in the injected mice. In conclusion, we revealed that intracerebral injection of synthetic full-length wild-type tau seeds prepared in the presence of dextran sulphate caused tau propagation in non-transgenic mice. These findings establish that propagation of tau assemblies does not require tau to be either mutant and/or overexpressed.

Polymorphism of Actin Paracrystals

In the muscle sarcomere and in certain specialized non-muscle cells actin filaments are organized in bundles or paracrystalline arrays. Structural studies of these naturally occurring filament arrays have been limited to about 3nm resolution, mainly due to inherent disorder of the specimen and/or difficulties with the preparation of these arrays for EM. Skeletal muscle G-actin can be induced to form synthetic filament paracrystals upon addition of non-physiological concentrations of Mg++ (e.g. 50mM) . The structural resolution obtained with these synthetic paracrystals has been of the same order (about 3nm) as that encountered with the naturally occurring filament arrays. Using a new method of induction, we have obtained synthetic paracrystals with two non-muscle actins which reveal structural detail to almost 2nm resolution (Figs. 1,2,3). While the same types of paracrystals were observed with Physarum and Acanthamoeba actin, skeletal muscle actin displayed a different polymorphism under identical conditions.