Cryo-EM structure and polymorphism of A\u03b2 amyloid fibrils purified from Alzheimer\u2019s brain tissue

Marius Kollmer,Marcus Fändrich,Angelika Schierhorn,Jay Rasmussen,Leonie Funk,Mathias Jucker,Matthias Schmidt,Christina J Sigurdson,Aref Bsoul,William Close

doi:10.1038/s41467-019-12683-8

Abstract

The formation of Aβ amyloid fibrils is a neuropathological hallmark of Alzheimer’s disease and cerebral amyloid angiopathy. However, the structure of Aβ amyloid fibrils from brain tissue is poorly understood. Here we report the purification of Aβ amyloid fibrils from meningeal Alzheimer’s brain tissue and their structural analysis with cryo-electron microscopy. We show that these fibrils are polymorphic but consist of similarly structured protofilaments. Brain derived Aβ amyloid fibrils are right-hand twisted and their peptide fold differs sharply from previously analyzed Aβ fibrils that were formed in vitro. These data underscore the importance to use patient-derived amyloid fibrils when investigating the structural basis of the disease.

Highlights

The formation of Aβ amyloid fibrils is a neuropathological hallmark of Alzheimer’s disease and cerebral amyloid angiopathy
Using cryo-electron microscopy we show that Aβ fibrils from brain tissue are polymorphic but share conserved structural features in terms of peptide fold and protofilament (PF) assembly
In this study we have analyzed the structural morphology of Aβ amyloid fibrils from Alzheimer’s disease (AD) brain tissue

Summary

Introduction

The formation of Aβ amyloid fibrils is a neuropathological hallmark of Alzheimer’s disease and cerebral amyloid angiopathy. We report the purification of Aβ amyloid fibrils from meningeal Alzheimer’s brain tissue and their structural analysis with cryo-electron microscopy We show that these fibrils are polymorphic but consist of structured protofilaments. Brain derived Aβ amyloid fibrils are right-hand twisted and their peptide fold differs sharply from previously analyzed Aβ fibrils that were formed in vitro. These data underscore the importance to use patient-derived amyloid fibrils when investigating the structural basis of the disease. Brainderived fibrils possess a twisted morphology with well-resolved cross-overs, reminiscent of in vitro formed Aβ fibrils (Fig. 1a) The handedness of their twist is right-handed as demonstrated by platinum side shadowing and analysis of the specimens with TEM or scanning electron microscopy (SEM) (Fig. 1b, c). Aβ fibrils from brain are proteinase K resistant and survive proteolytic conditions that readily degrade in vitro formed Aβ fibrils (Supplementary Fig. 4)

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