Affiliations: [a] The Birchall Centre, Lennard-Jones Laboratories, Keele University, Staffordshire, UK | [b] School of Engineering, University of Warwick, Coventry, UK | [c] Materials Science Engineering, University of Florida, Gainesville, FL, USA | [d] Cavendish Laboratory, University of Cambridge, Cambridge, CB3 0HE, UK
Correspondence:
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Correspondence to: Dr. Christopher Exley, The Birchall Centre, Lennard-Jones Laboratories, Keele University, Staffordshire, ST5 5BG, UK. Tel.: +44 1782 734080; E-mail: [email protected].
Abstract: Several amyloidogenic proteins including insulin, β-lactoglobulin, and albumin form spherulites in vitro under non-physiological conditions. These micrometer-sized, roughly spherical structures are composed of ordered arrays of amyloid fibrils in radial arrangements which, characteristically, show a typical Maltese cross pattern of light extinction under the polarizing microscope. The physiological significance of amyloid spherulites is unknown though in Alzheimer's disease, senile plaques composed primarily of β sheets of amyloid-β (Aβ)42 have, very occasionally, been shown to give a Maltese cross pattern of light extinction under crossed polarizers. Herein we describe the first observation of the formation in vitro of spherulites of Aβ42. They were formed under near-physiological conditions in which the β sheet conformation of pre-formed aggregates of Aβ42 had been abolished following the addition of an excess of copper. Incubation of these preparations at 37°C for up to 9 months resulted in the formation of globular structures, 5–20 μm in diameter, which exhibited a Maltese cross pattern of light extinction typical of spherulites. Near-identical spherulitic structures were also observed in abundance in 30 μm thick sections of Alzheimer's disease brain tissue. Synchrotron x-ray fluorescence showed that the location of these spherulites in AD tissue coincided with locally elevated concentrations of tissue copper. The formation in vitro of spherulites of Aβ42 which morphologically appeared analogous to spherulitic structures observed in vivo strongly supports the hypothesis that spherulites and senile plaques in AD tissue are one and the same structures and that their ultimate formation may involve copper.
