title: Cellular copper import by nanocarrier systems, intracellular availability, and effects on amyloid beta peptide secretion.
abstract: Studies in animals have reported that normalized or elevated Cu levels can inhibit or even remove Alzheimer's disease-related pathological plaques and exert a desirable amyloid-modifying effect. We tested engineered nanocarriers composed of diverse core-shell architectures to modulate Cu levels under physiological conditions through bypassing the cellular Cu uptake systems. Two different nanocarrier systems were able to transport Cu across the plasma membrane of yeast or higher eukaryotic cells, CS-NPs (core-shell nanoparticles) and CMS-NPs (core-multishell nanoparticles). Intracellular Cu levels could be increased up to 3-fold above normal with a sublethal dose of carriers. Both types of carriers released their bound guest molecules into the cytosolic compartment where they were accessible for the Cu-dependent enzyme SOD1. In particular, CS-NPs reduced Abeta levels and targeted intracellular organelles more efficiently than CMS-NPs. Fluorescently labeled CMS-NPs unraveled a cellular uptake mechanism, which depended on clathrin-mediated endocytosis in an energy-dependent manner. In contrast, the transport of CS-NPs was most likely driven by a concentration gradient. Overall, nanocarriers depending on the nature of the surrounding shell functioned by mediating import of Cu across cellular membranes, increased levels of bioavailable Cu, and affected Abeta turnover. Our studies illustrate that Cu-charged nanocarriers can achieve a reasonable metal ion specificity and represent an alternative to metal-complexing agents. The results demonstrate that carrier strategies have potential for the treatment of metal ion deficiency disorders.
authors.affiliation: Freie Universitat Berlin, Institut fur Chemie und Biochemie, Thielallee 63, D-14195 Berlin, Germany.
authors.forename: Carina
authors.initials: C
authors.lastname: Treiber
authors.forename: Mohiuddin Abdul
authors.initials: MA
authors.lastname: Quadir
authors.forename: Philipp
authors.initials: P
authors.lastname: Voigt
authors.forename: Michal
authors.initials: M
authors.lastname: Radowski
authors.forename: Shangjie
authors.initials: S
authors.lastname: Xu
authors.forename: Lisa-Marie
authors.initials: LM
authors.lastname: Munter
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Bayer
authors.forename: Michael
authors.initials: M
authors.lastname: Schaefer
authors.forename: Rainer
authors.initials: R
authors.lastname: Haag
authors.forename: Gerd
authors.initials: G
authors.lastname: Multhaup