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

The cytotoxicity of the amyloid beta (A beta) 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 A beta. In this work, fully atomistic molecular dynamics (MD) simulations are exploited to obtain direct molecular insights into the process of early A beta 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 A beta 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 A beta small oligomers modified with glycation. Our combined results imply that glycation consolidates A beta 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.