Tachykinin Neuropeptides and Amyloid β (25-35) Assembly: Friend or Foe?

Abstract

Amyloid β (Aβ) protein is responsible for Alzheimer's disease, and one of its important fragments, Aβ(25-35), is found in the brain and has been shown to be neurotoxic. Tachykinin neuropeptides, including Neuromedin K (NK), Kassinin, and Substance P, have been reported to reduce Aβ(25-35)'s toxicity in cells even though they share similar primary structures with Aβ(25-35). Here, we seek to understand the molecular mechanisms of how these peptides interact with Aβ(25-35) and to shed light on why some peptides with similar primary structures are toxic and others nontoxic. We use both experimental and computational methods, including ion mobility mass spectrometry and enhanced-sampling replica-exchange molecular dynamics simulations, to study the aggregation pathways of Aβ(25-35), NK, Kassinin, Substance P, and mixtures of the latter three with Aβ(25-35). NK and Substance P were observed to remove the higher-order oligomers (i.e., hexamers and dodecamers) of Aβ(25-35), which are related to its toxicity, although Substance P did so more slowly. In contrast, Kassinin was found to promote the formation of these higher-order oligomers. This result conflicts with what is expected and is elaborated on in the text. We also observe that even though they have significant structural homology with Aβ(25-35), NK, Kassinin, and Substance P do not form hexamers with a β-sheet structure like Aβ(25-35). The hexamer structure of Aβ(25-35) has been identified as a cylindrin, and this structure has been strongly correlated to toxic species. The reasons why the three tachykinin peptides behave so differently when mixed with Aβ(25-35) are discussed.