Aβ amyloidogenesis is reported to occur via a nucleated polymerization mechanism, if so the energetically unfavorable oligomeric nucleus should be very hard to detect. However, many laboratories have detected early non-fibrillar Aβ oligomers without observing amyloid fibrils, suggesting a mechanistic revision may be needed. Herein, we introduce Cys-Cys-Aβ1-40 that cannot bind to the latent fluorophore FlAsH as a monomer, but is capable of binding FlAsH as an non-fibrillar oligomer or as a fibril, rendering the conjugates fluorescent. FlAsH monitoring of Cys-Cys-Aβ1-40 aggregation provides compelling evidence that Aβ1-40 very rapidly and efficiently forms spherical oligomers in vitro (85% yield) that are kinetically competent to slowly convert to amyloid fibrils by a nucleated conformational conversion mechanism (seedable). Moreover, this methodology demonstrated that plasmalogen ethanolamine vesicles eliminate the proteotoxicity-associated oligomerization phase of Aβ amyloidogenesis, while allowing fibril formation, rationalizing how low plasmalogen ethanolamine levels in the brain are epidemiologically linked to Alzheimer’s disease.

Protein misfolding and/or aggregation has been implicated in several human diseases, such as Alzheimer’s and Parkinson’s diseases and familial amyloid polyneuropathy. These maladies are referred to as amyloid diseases, because they are named after the cross-β-sheet amyloid fibril aggregates or deposits common to these diseases. Epigallocatechin-3-gallate (EGCG), the principal polyphenol present in green tea, has been shown to be effective at preventing aggregation and is able to remodel amyloid fibrils comprising different amyloidogenic proteins, although the mechanistic underpinnings are unclear. Herein, we work towards an understanding of the molecular mechanism(s) by which EGCG remodels mature amyloid fibrils made up of Aβ1–40, IAPP8–24, or Sup35NM7–16. We show that EGCG amyloid remodeling activity in vitro is dependent on auto-oxidation of the EGCG. Oxidized and unoxidized EGCG binds to amyloid fibrils, preventing the binding of thioflavin T. This engagement of the hydrophobic binding sites in Aβ1–40, IAPP8–24, or Sup35NM7–16 amyloid fibrils seems to be sufficient to explain the majority of the amyloid remodeling observed by EGCG treatment, although how EGCG oxidation drives remodeling remains unclear. Oxidized EGCG molecules react with free amines within the amyloid fibril through the formation of Schiff bases, cross-linking the fibrils, which may prevent dissociation and toxicity, but these aberrant post-translational modifications do not appear to be the major driving force for amyloid remodeling by EGCG treatment. These insights into the molecular mechanism of action of EGCG provide boundary conditions for exploring amyloid remodeling in more detail.

No abstract

We report knitted fabrics made from highly conductive stretchable fibers. The maximum initial conductivity of fibers synthesized by wet spinning was 17460 S cm(-1) with a rupture tensile strain of 50%. The maximum strain could be increased to 490% by decreasing the conductivity to 236 S cm(-1). The knitted fabric was mechanically and electrically reversible up to 100% tensile strain when coated by poly(dimethylsiloxane). The normalized resistance of the poly(dimethylsiloxane)-coated fabric decreased to 0.65 at 100% strain.