Glycation induces conformational changes in the amyloid-β peptide and enhances its aggregation propensity: molecular insights.

The cytotoxicity of the amyloid beta (Aβ) peptide, implicated in the pathogenesis of Alzheimer's disease (AD), can be enhanced by its post-translational glycation, a series of non-enzymatic reactions with reducing sugars and reactive dicarbonyls. However, little is known about the underlying mechanisms that potentially enhance the cytotoxicity of the advanced glycation modified Aβ. In this work, fully atomistic molecular dynamics (MD) simulations are exploited to obtain direct molecular insights into the process of early Aβ self-assembly in the presence and absence of glycated lysine residues. Analyses of data exceeding cumulative timescales of 1 microsecond for each system reveal that glycation results in a stronger enthalpy of association between Aβ monomers and lower conformational entropy, in addition to a sharp overall increase in the beta-sheet content. Further analyses reveal that the enhanced interactions originate, in large part, due to markedly stronger, as well as new, inter-monomer salt bridging propensities in the glycated variety. Interestingly, these conformational and energetic effects are broadly reflected in preformed protofibrillar forms of Aβ small oligomers modified with glycation. Our combined results imply that glycation consolidates Aβ self-assembly regardless of its point of occurrence in the pathway. They provide a basis for further mechanistic studies and therapeutic endeavors that could potentially result in novel ways of combating AGE related AD progression.