Atomic Details of the Interactions of Glycosaminoglycans with Amyloid-β Fibrils

The amyloid plaques associated with Alzheimer's disease (AD) comprise fibrillar amyloid-β (Aβ) peptides as well as non-protein factors including glycosaminoglycan (GAG) polysaccharides. GAGs affect the kinetics and pathway of Aβ self-assembly and can impede fibril clearance; thus, they may be accessory molecules in AD. Here we report the first high-resolution details of GAG-Aβ fibril interactions from the perspective of the saccharide. Binding analysis indicated that the GAG proxy heparin has a remarkably high affinity for Aβ fibrils with 3-fold cross-sectional symmetry (3Q). Chemical synthesis of a uniformly 13C-labeled octasaccharide heparin analogue enabled magic-angle spinning solid-state NMR of the GAG bound to 3Q fibrils, and measurements of dynamics revealed a tight complex in which all saccharide residues are restrained without undergoing substantial conformational changes. Intramolecular 13C-15N dipolar dephasing is consistent with close (<5 Å) contact between GAG anomeric position(s) and one or more histidine residues in the fibrils. These data provide a detailed model for the interaction between 3Q-seeded Aβ40 fibrils and a major non-protein component of AD plaques, and they reveal that GAG-amyloid interactions display a range of affinities that critically depend on the precise details of the fibril architecture

Electroactive Silk Fibroin Films for Electrochemically Enhanced Delivery of Drugs

Biomaterials capable of controlling the delivery of drugs have the potential to treat a variety of conditions. Herein, the preparation of electrically conductive silk fibroin film‐based drug delivery devices is described. Casting aqueous solutions of Bombyx mori silk fibroin, followed by drying and annealing to impart β‐sheets to the silk fibroin, assure that the materials are stable for further processing in water; and the silk fibroin films are rendered conductive by generating an interpenetrating network of a copolymer of pyrrole and 3‐amino‐4‐hydroxybenzenesulfonic acid in the silk fibroin matrix (characterized by a variety of techniques including circular dichroism, Fourier‐transform infrared spectroscopy, nuclear magnetic resonance, Raman spectroscopy, resistance measurements, scanning electron microscopy‐energy dispersive X‐ray spectroscopy, thermogravimetric analysis, X‐ray diffraction, and X‐ray photoelectron spectroscopy). Fibroblasts adhere on the surface of the biomaterials (viability assessed using an (3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide) assay and visualized using a confocal microscope), and a fluorescently labeled drug (Texas‐Red Gentamicin) can be loaded electrochemically and released (µg cm−2 quantities) in response to the application of an electrical stimulus