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.

Systemic amyloidosis is caused by the misfolding of a circulating amyloid precursor protein and the deposition of amyloid fibrils in multiple organs. Chemical and biophysical analysis of amyloid fibrils from human AL and murine AA amyloidosis reveal the same fibril morphologies in different tissues or organs of one patient or diseased animal. The observed structural similarities concerned the fibril morphology, the fibril protein primary and secondary structures, the presence of post-translational modifications and, in case of the AL fibrils, the partially folded characteristics of the polypeptide chain within the fibril. Our data imply for both analyzed forms of amyloidosis that the pathways of protein misfolding are systemically conserved; that is, they follow the same rules irrespective of where inside one body fibrils are formed or accumulated.

Systemic amyloidosis is caused by the misfolding of ac irculating amyloid precursor protein and the deposition of amyloid fibrils in multiple organs.C hemical and biophysical analysis of amyloid fibrils from human AL and murine AA amyloidosis reveal the same fibril morphologies in different tissues or organs of one patient or diseased animal. The observed structural similarities concerned the fibril morphology,t he fibril protein primary and secondary structures,t he presence of post-translational modifications and, in case of the AL fibrils,t he partially folded characteristics of the polypeptide chain within the fibril. Our data imply for both analyzed forms of amyloidosis that the pathways of protein misfolding are systemically conserved;t hat is,t hey follow the same rules irrespective of where inside one body fibrils are formed or accumulated.

Polymorphismus ist ein weit verbreitetes Merkmal von in vitro gebildeten Amyloid-artigen Fibrillen, doch blieb bislang unklar,obAmyloidfibrillen in vivo ebenso von diesem Phänomen betroffen sind. Hier zeigen wir,d ass sich verschiedene innerhalb eines Patienten gebildete Amyloidfibrillen erheblich in ihrer Morphologie unterscheiden kçnnen. Wire rhalten diesen Befund mit Amyloidfibrillen aus verschiedenen Organen, bestehend aus nicht-homologen Polypeptidketten sowie aus menschlichem und tierischem Gewebe.Unabhängig von Amyloidtyp und -herkunft finden wir,d ass in vivo gebildete Amyloidfibrillen signifikant polymorphe Eigenschaften aufweisen. Diese Daten lassen darauf schließen, dass die chemischen Grundlagen jener Reaktionen, die in der Selbstorganisation zu Fibrillen zu Polymorphismus führen, in vivo und in vitro grundsätzlichkonserviert sind.