The fuzzy coat of pathological human Tau fibrils is a two-layered polyelectrolyte brush

Abstract

The structure and properties of amyloid-like Tau fibrils accumulating in neurodegenerative diseases have been debated for decades. Although the core of Tau fibrils assembles from short β-strands, the properties of the much longer unstructured Tau domains protruding from the fibril core remain largely obscure. Applying immunogold transmission EM, and force-volume atomic force microscopy (AFM), we imaged human Tau fibrils at high resolution and simultaneously mapped their mechanical and adhesive properties. Tau fibrils showed a ≈16-nm-thick fuzzy coat that resembles a two-layered polyelectrolyte brush, which is formed by the unstructured short C-terminal and long N-terminal Tau domains. The mechanical and adhesive properties of the fuzzy coat are modulated by electrolytes and pH, and thus by the cellular environment. These unique properties of the fuzzy coat help in understanding how Tau fibrils disturb cellular interactions and accumulate in neurofibrillary tangles.protein aggregation | Alzheimer's disease | paired helical filaments

Tau protein liquid–liquid phase separation can initiate tau aggregation

“…Besides microtubule‐related functions, tau droplets could interact with other polymer‐gel entities in the cell (e.g., the nuclear pore complex nucleoporins) or facilitate the transport of molecules partitioning into the droplets. In fact, the liquid phase separation of the unstructured N‐terminal half of tau may be related to some of the earlier observations showing a polymer‐brush‐like projection of the N‐termini from the surface of microtubules (Vallee & Borisy, 1977; Gustke et al , 1994) as well as from fibrillary tau aggregates (Wegmann et al , 2013). These polymer brushes can to some extent resemble two‐dimensional droplets with similar gel‐like properties.…”

“…The longest isoform of tau in the human CNS contains a MTB region that contains four pseudo‐repeats (R1–R4) plus flanking proline‐rich regions (P1, P2, and P3; Gustke et al , 1994), a shorter (≈40 aa) C‐terminal tail, and a long (≈250 aa) flexible N‐terminal half of tau, which projects from the surface of microtubules in the MT‐bound state (Goode et al , 1997), and forms a polyelectrolyte brush around fibrillary aggregates of tau (Sillen et al , 2005; Wegmann et al , 2013). The lack of a fixed tertiary protein structure classifies tau as an intrinsically disordered protein (IDP).…”

A Food and Drug Administration-approved Asthma Therapeutic Agent Impacts Amyloid β in the Brain in a Transgenic Model of Alzheimer Disease

“…Analysis of A␤ 42 Fibril Formation by Transmission Electron Microscopy-The antifibrillogenic properties of cromolyn was confirmed by performing TEM analysis as previously described (33). Briefly, synthetic A␤ 42 was dissolved in PBS at a concentration of 0.2 mg/ml for 48 h at 37°C, with or without addition of Cromolyn Sodium at a concentration of either 5 nM or 500 nM.…”

Update on Alzheimer's Disease Therapy and Prevention Strategies

“…Paired helical filaments (PHFs) consist of the repeat regions at the core and the N and C termini forming a "fuzzy coat" (62). Aggregated tau has been described as a two-layered polyelectrolyte brush because of the heterogeneity of the N-and C-terminal structures (63).…”