Visualizing and trapping transient oligomers in amyloid assembly pathways

Abstract

Oligomers which form during amyloid fibril assembly are considered to be key contributors towards amyloid disease. However, understanding how such intermediates form, their structure, and mechanisms of toxicity presents significant challenges due to their transient and heterogeneous nature. Here, we discuss two different strategies for addressing these challenges: use of (1) methods capable of detecting lowly-populated species within complex mixtures, such as NMR, single particle methods (including fluorescence and force spectroscopy), and mass spectrometry; and (2) chemical and biological tools to bias the amyloid energy landscape towards specific oligomeric states. While the former methods are well suited to following the kinetics of amyloid assembly and obtaining low-resolution structural information, the latter are capable of producing oligomer samples for high-resolution structural studies and inferring structure-toxicity relationships. Together, these different approaches should enable a clearer picture to be gained of the nature and role of oligomeric intermediates in amyloid formation and disease.

How epigallocatechin gallate binds and assembles oligomeric forms of human alpha-synuclein

“…Here, we use liquid-state NMR spectroscopy ( 30 , 31 ) to show that EGCG binds to monomeric and oligomeric αSN. We find that monomeric and oligomeric αSN bind 54 and 7 EGCG molecules, respectively, and that EGCG slowly (over a 4-day period) binds to and immobilizes all protein residues.…”

In Situ Continuous Wave Electron Paramagnetic Resonance Investigation of the Amyloid Aggregation of Parkinson’s Protein Alpha-Synuclein—the Second Spin-Label Position

“…Amyloid aggregation is a critical step in neurodegenerative disease and recent emphasis on oligomeric intermediates in this process as disease active agents has triggered the search for novel methods to measure such intermediates, see for example [1,2]. Alpha-synuclein (αS) is an interesting example, as it is a functional protein in the brain, where it is suggested to be involved in neuronal-vesicle fusion to the synapse, and thereby important in the neurotransmitter release in the synapse [3,4].…”

Gallium nanoparticles as novel inhibitors of Aβ40 aggregation

“…[2][3][4] Amyloid formation of Aβ is typically viewed as a nucleated polymerization process, manifested by an initial lag phase in which the oligomeric nuclei are formed, followed by a rapid growth phase during which the nuclei grow by the addition of monomers to form fibrillar structures. [5][6] Moreover, amyloid oligomers has also shown to form hetero-oligomers by interacting with its isoforms or other proteins. 5,7 Therefore great effort have been devoted to characterized oligomers to better understand amyloid mechanism and conceived plausible therapeutics alternatives.…”

“…5,7 Therefore great effort have been devoted to characterized oligomers to better understand amyloid mechanism and conceived plausible therapeutics alternatives. 4,6 One of the plausible therapeutic strategies for treating the disease is to inhibit the formation of toxic Aβ aggregate species. As such, a wide variety of amyloid inhibitors that can prevent the formation of Aβ aggregates, e.g., small organic compounds and designed peptides, have been reported.…”