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

Abstract

<jats:title>Abstract</jats:title> <jats:p>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.</jats:p> <jats:p>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 one 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.</jats:p> <jats:p>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.</jats:p>

Phosphorylation of endogenous α-synuclein induced by extracellular seeds initiates at the pre-synaptic region and spreads to the cell body

“…It is thought that tau and TDP-43, as well as α-synuclein, propagate through the brain in a prion-like manner 5 , 55 – 57 . As described above, α-synuclein is abundant in presynaptic regions, whereas tau is abundant in neurites and TDP-43 is mostly localized in the nucleus.…”

Intracellular Tau Fragment Droplets Serve as Seeds for Tau Fibrils

“…The events observed in our cells may mimic such human tau pathology. Although the question of what seed tau is needs to be carefully addressed, dextran tau forms granular tau oligomers but not long fibrils (Figure S7), and the dextran formed tau aggregates enhanced the propagation of endogenous tau in C57BL/6J mice 106 . Aggregates of dGAE increased endogenous tau phosphorylation 107 , and phosphorylated high-molecular-weight tau derived from Alzheimer’s disease brain had tau seeding activity 62 .…”

Novel aspects of the phosphorylation and structure of pathological tau: implications for tauopathy biomarkers

“…The N‐terminal domain, including the positively charged proline‐rich region, and the C‐terminal domain inhibit the spontaneous assembly of full‐length recombinant tau. Therefore, recombinant full‐length tau assembly requires polyanionic assembly accelerators in vitro , such as heparin and dextran sulfate [ 47 , 48 ]. However, they have different structures from those in human patients, making it difficult to elucidate the molecular mechanisms underlying human tauopathies [ 49 , 50 ].…”