Propagation of Tau aggregates

Abstract

Since 2009, evidence has accumulated to suggest that Tau aggregates form first in a small number of brain cells, from where they propagate to other regions, resulting in neurodegeneration and disease. Propagation of Tau aggregates is often called prion-like, which refers to the capacity of an assembled protein to induce the same abnormal conformation in a protein of the same kind, initiating a self-amplifying cascade. In addition, prion-like encompasses the release of protein aggregates from brain cells and their uptake by neighbouring cells. In mice, the intracerebral injection of Tau inclusions induced the ordered assembly of monomeric Tau, followed by its spreading to distant brain regions. Short fibrils constituted the major species of seed-competent Tau. The existence of several human Tauopathies with distinct fibril morphologies has led to the suggestion that different molecular conformers (or strains) of aggregated Tau exist.

Keywords: Alzheimer’s disease; Amyloid; Cell-to-cell spreading; Disease propagation; Prion-like; Protein strains; Tau; Tauopathies.

Figures

Fig. 1

Human brain Tau isoforms and MAPT mutations. aMAPT and the six Tau isoforms expressed in adult human brain. MAPT consists of 16 exons (E). Alternative mRNA splicing of E2 (red), E3 (green), and E10 (yellow) gives rise to six tau isoforms (amino acids 352–441). Constitutively spliced exons (E1, E4, E5, E7, E9, E11, E12, E13) are shown in blue. E0, which is part of the promoter, and E14 are noncoding (white). E6 and E8 (violet) are not transcribed in human brain. E4a (orange) is only expressed in the peripheral nervous system. The repeats (R1-R4) are shown, with three isoforms having four repeats each (4R) and three isoforms having three repeats each (3R). Each repeat is 31 amino acids in length. Exons and introns are not drawn to scale. b Mutations in MAPT in cases of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17 T); 49 coding region mutations and 10 intronic mutations flanking E10 are shown

Fig. 2

Induction of filamentous Tau pathology in mice transgenic for wild-type human Tau (line ALZ17) following injection with brain extracts from symptomatic mice transgenic for human mutant P301S tau. Staining of the hippocampal CA3 region of 18-month-old ALZ17 mice with anti-Tau antibodies AT8 and AT100 and Gallyas-Braak silver. Non-injected (left), 15 months after injection of brain extract from non-transgenic control mice (middle) and 15 months after injection with brain extract from 6-month-old mice transgenic for human P301S Tau (right). The sections were counterstained with haematoxylin. Scale bar = 50 μm

Fig. 3

Seeding of Tau aggregation with sucrose gradient fractions from the brains of mice transgenic for human mutant P301S Tau in a cell-based assay. The mice were aged 4.4 weeks (no symptoms, no Tau filaments) or 24.4 weeks (symptoms, abundant Tau filaments). Sucrose gradient fractions were used to seed aggregation of Tau in HEK cells expressing 1N4R Tau with the P301S mutation. The pellet from a 100,000 g spin of seeded cells was analysed by Western blotting for total Tau and Tau phosphorylated at S202/T205 (anti-Tau antibodies DA9 and AT8). Filamentous Tau runs at approximately 68 kDa (HMW, high-molecular weight); non-filamentous Tau runs at approximately 59 kDa (LMW, low-molecular weight). The positive control consisted in seeding with sarkosyl-extracted Tau from unfractionated brains of symptomatic transgenic P301S Tau mice and the normalised positive control was seeding with sarkosyl-extracted Tau from symptomatic mice, normalised for total Tau levels relative to those of the sucrose gradient fractions. Seeding ability correlated with the presence of the 64 kDa band in 24.4-week-old mice (20–50% sucrose gradient fractions). No seeding was observed upon addition of sucrose gradient fractions from the brains of 4.4-week-old mice