Insights into Formation and Structure of Aβ Oligomers Cross-Linked via Tyrosines

Abstract

Alzheimer's disease (AD) pathology is hypothesized to be triggered by amyloid β-protein (Aβ) assembly into oligomers. Oligomer size distributions of both predominant Aβ alloforms, Aβ and Aβ, can be determined in vitro using cross-linking followed by gel electrophoresis. Cross-linking, which can occur in vivo in the presence of copper and hydrogen peroxide, was recently shown to stabilize Aβ oligomers by inhibiting their conversion into fibrils. Whereas several studies showed that cross-linking is facilitated by dityrosine bond formation, the molecular-level mechanism of cross-linking remains unclear. Here, we use efficient discrete molecular dynamics with DMD4B-HYDRA force field to examine the effect of cross-linking via tyrosines on Aβ oligomer formation. Our results show that cross-linking via tyrosines promotes Aβ self-assembly, in particular that of Aβ, but does not account for cross-linked oligomers larger than Aβ trimers and Aβ tetramers. Cross-linking via tyrosines profoundly alters Aβ and Aβ oligomer conformations by increasing the solvent exposure of hydrophobic residues, resulting in elongated oligomeric morphologies that differ from globular structures of noncross-linked oligomers. When compared to available experimental data, our findings imply that amino acids other than tyrosines are involved in Aβ cross-linking, a proposition that is currently under investigation.

A novel crosslinking protocol stabilizes amyloid β oligomers capable of inducing Alzheimer's‐associated pathologies

“…We chose DFDNB for AbO stabilization due to preliminary indications that it stabilizes AbOs > 50 kDa (Grimm et al 2007), which have been demonstrated AD relevant (Gong et al 2003;Lacor et al 2004Lacor et al , 2007Lesne et al 2006;Noguchi et al 2009;Upadhaya et al 2012;Velasco et al 2012;Mc Donald et al 2015). Current AbO stabilization protocols, PICUP and dityrosine crosslinking, are ineffective in this size range (Ono et al 2009;Williams et al 2015;Hayden et al 2017;Zhang et al 2017), thereby limiting analysis.…”

The Amyloid-β Oligomer Hypothesis: Beginning of the Third Decade

“…Furthermore, dityrosine crosslinked proteins are found to be prevalent in AD brain and CSF [ 160 ]. Molecular dynamics simulations predict that dityrosine crosslinking promotes Aβ self-assembly, at least up to tetramers [ 162 ]. In one study, copper was found to stabilize Aβ in an oligomeric conformation sufficiently to enable 3D structural characterization by small-angle x-ray scattering [ 163 ].…”

Metal- and UV- Catalyzed Oxidation Results in Trapped Amyloid-β Intermediates Revealing that Self-Assembly Is Required for Aβ-Induced Cytotoxicity

“…Previous studies have suggested that DiY cross-linking can facilitate Aβ assembly ( Atwood et al., 2004 ; Yoburn et al., 2003 ; Barnham et al., 2003 ; Zhang et al., 2017 ) or inhibit or slow Aβ self-assembly ( Smith et al., 2007 ; Gu et al., 2018 ) or stabilize assemblies ( Vazquez et al., 2019 ). Importantly, it has been shown that copper influences self-assembly in different ways depending on the concentration and ratio ( Matheou et al., 2015 ; Sarell et al., 2010 ), which may go some way to explaining these inconsistencies.…”