Unraveling the complexity of amyloid polymorphism using gold nanoparticles and cryo-EM.

Abstract:

:Increasing evidence suggests that amyloid polymorphism gives rise to different strains of amyloids with distinct toxicities and pathology-spreading properties. Validating this hypothesis is challenging due to a lack of tools and methods that allow for the direct characterization of amyloid polymorphism in hydrated and complex biological samples. Here, we report on the development of 11-mercapto-1-undecanesulfonate-coated gold nanoparticles (NPs) that efficiently label the edges of synthetic, recombinant, and native amyloid fibrils derived from different amyloidogenic proteins. We demonstrate that these NPs represent powerful tools for assessing amyloid morphological polymorphism, using cryogenic transmission electron microscopy (cryo-EM). The NPs allowed for the visualization of morphological features that are not directly observed using standard imaging techniques, including transmission electron microscopy with use of the negative stain or cryo-EM imaging. The use of these NPs to label native paired helical filaments (PHFs) from the postmortem brain of a patient with Alzheimer's disease, as well as amyloid fibrils extracted from the heart tissue of a patient suffering from systemic amyloid light-chain amyloidosis, revealed a high degree of homogeneity across the fibrils derived from human tissue in comparison with fibrils aggregated in vitro. These findings are consistent with, and strongly support, the emerging view that the physiologic milieu is a key determinant of amyloid fibril strains. Together, these advances should not only facilitate the profiling and characterization of amyloids for structural studies by cryo-EM, but also pave the way to elucidate the structural basis of amyloid strains and toxicity, and possibly the correlation between the pathological and clinical heterogeneity of amyloid diseases.

authors

Cendrowska U,Silva PJ,Ait-Bouziad N,Müller M,Guven ZP,Vieweg S,Chiki A,Radamaker L,Kumar ST,Fändrich M,Tavanti F,Menziani MC,Alexander-Katz A,Stellacci F,Lashuel HA

doi

10.1073/pnas.1916176117

subject

Has Abstract

pub_date

2020-03-24 00:00:00

pages

6866-6874

issue

12

eissn

0027-8424

issn

1091-6490

pii

1916176117

journal_volume

117

pub_type

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