Polymorphism of Amyloid Fibrils In Vivo

Abstract

Polymorphism is a wide-spread feature of amyloid-like fibrils formed in vitro, but it has so far remained unclear whether the fibrils formed within a patient are also affected by this phenomenon. In this study we show that the amyloid fibrils within a diseased individual can vary considerably in their three-dimensional architecture. We demonstrate this heterogeneity with amyloid fibrils deposited within different organs, formed from sequentially non-homologous polypeptide chains and affecting human or animals. Irrespective of amyloid type or source, we found in vivo fibrils to be polymorphic. These data imply that the chemical principles of fibril assembly that lead to such polymorphism are fundamentally conserved in vivo and in vitro.

Keywords: Alzheimer's disease; Parkinson's disease; prions; protein folding; systemic amyloidosis.

Figure 1

A) Negative-stain TEM image of the fibrils extracted from the AL case 1 heart tissue samples. Scale bar: 100 nm. B) Coomassie-stained denaturing polyacrylamide gel run under reducing conditions showing the last five washing steps with Tris-EDTA and the first five extraction steps in water. The asterisk indicates the AL protein. Arrow heads show gel border.

Figure 2

A) Schematic representation of the parameters fibril width, pitch and width at the crossover based on the electron microscopy data bank entry EMD-3132.^[12] Negative stain TEM images of AL amyloid fibrils (case 1, B) and plot of the structural parameters (C). Negative stain TEM images of AL amyloid fibrils (case 2, D) and plot of the structural parameters (E). Scale bar is 100 nm.

Figure 3

Negative stain mt-ATTR amyloid fibrils from human heart (A) and of AA amyloid fibrils from mouse spleen (B), fox spleen (C) and goat uterus (D). Scale bar is 100 nm.