Abstract
Alzheimer’s disease is associated with the formation of toxic aggregates of amyloid beta (Aβ) peptides. Despite tremendous efforts, our understanding of the molecular mechanisms of aggregation, as well as cofactors that might influence it, remains incomplete. The small cyclic neuropeptide somatostatin-14 (SST14) was recently found to be the most selectively enriched protein in human frontal lobe extracts that binds Aβ42 aggregates. Furthermore, SST14’s presence was also found to promote the formation of toxic Aβ42 oligomers in vitro. In order to elucidate how SST14 influences the onset of Aβ oligomerization, we performed all-atom molecular dynamics simulations of model mixtures of Aβ42 or Aβ40 peptides with SST14 molecules and analyzed the structure and dynamics of early-stage aggregates. For comparison we also analyzed the aggregation of Aβ42 in the presence of arginine vasopressin (AVP), a different cyclic neuropeptide. We observed the formation of self-assembled aggregates containing the Aβ chains and small cyclic peptides in all mixtures of Aβ42–SST14, Aβ42–AVP, and Aβ40–SST14. The Aβ42–SST14 mixtures were found to develop compact, dynamically stable, but small aggregates with the highest exposure of hydrophobic residues to the solvent. Differences in the morphology and dynamics of aggregates that comprise SST14 or AVP appear to reflect distinct (1) regions of the Aβ chains they interact with; (2) propensities to engage in hydrogen bonds with Aβ peptides; and (3) solvent exposures of hydrophilic and hydrophobic groups. The presence of SST14 was found to impede aggregation in the Aβ42–SST14 system despite a high hydrophobicity, producing a stronger “sticky surface” effect in the aggregates at the onset of Aβ42–SST14 oligomerization.
Highlights
Alzheimer’s disease (AD) is one of the most devastating neurodegenerative disorders of our time due to its high prevalence in the aging population, the challenges of early diagnosis and the lack of efficient therapeutics
Eight Aβ42 or Aβ40 chains and eight SST14 or arginine vasopressin (AVP) molecules were placed in the simulation box in random positions, as outlined in the Methods section
The examples displayed below originate from trajectories Aβ42-SST14-I, Aβ42-AVP-II, and Aβ40-SST14II
Summary
Alzheimer’s disease (AD) is one of the most devastating neurodegenerative disorders of our time due to its high prevalence in the aging population, the challenges of early diagnosis and the lack of efficient therapeutics. Insights into the molecular mechanisms of misfolding and aggregation, as well as co-factors that might influence these processes, remain incomplete Contributing to this status quo is a high level of heterogeneity in regards to both the building blocks and the architecture of early oligomeric assemblies. Recent modeling studies [21,22] indicate that accumulation of subtle structural perturbations of early aggregates at the onset of the oligomerization process may result in distinct aggregation pathways at later, more advanced stages of Aβ oligomerization Both experimental and theoretical evidence suggests that molecular events occurring early in the process of aggregation play a key role in determining both the structure and toxicity of Aβ oligomers [14]
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