Premium
Inhibition of the formation of amyloid β‐protein fibrils using biocompatible nanogels as artificial chaperones
Author(s) -
Ikeda Keisuke,
Okada Takuma,
Sawada Shin-ichi,
Akiyoshi Kazunari,
Matsuzaki Katsumi
Publication year - 2006
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2006.11.009
Subject(s) - pullulan , chemistry , fibril , biophysics , monomer , nanogel , random coil , cytotoxicity , biocompatible material , amyloid (mycology) , molecule , biochemistry , protein secondary structure , drug delivery , polysaccharide , organic chemistry , in vitro , polymer , medicine , inorganic chemistry , biomedical engineering , biology
The formation of fibrils by amyloid β‐protein (Aβ) is considered as a key step in the pathology of Alzheimer's disease (AD). Inhibiting the aggregation of Aβ is a promising approach for AD therapy. In this study, we used biocompatible nanogels composed of a polysaccharide pullulan backbone with hydrophobic cholesterol moieties (cholesterol‐bearing pullulan, CHP) as artificial chaperones to inhibit the formation of Aβ‐(1–42) fibrils with marked amyloidgenic activity and cytotoxicity. The CHP‐nanogels incorporated up to 6–8 Aβ‐(1–42) molecules per particle and induced a change in the conformation of Aβ from a random coil to α‐helix‐ or β‐sheet‐rich structure. This structure was stable even after a 24‐h incubation at 37 °C and the aggregation of Aβ‐(1–42) was suppressed. Furthermore, the dissociation of the nanogels caused by the addition of methyl‐β‐cyclodextrin released monomeric Aβ molecules. Nanogels composed of amino‐group‐modified CHP (CHPNH 2 ) with positive charges under physiological conditions had a greater inhibitory effect than CHP‐nanogels, suggesting the importance of electrostatic interactions between CHPNH 2 and Aβ for inhibiting the formation of fibrils. In addition, CHPNH 2 nanogels protected PC12 cells from Aβ toxicity.