Fibril formation is associated with essential biological functions, such as the storage of peptide hormones, as well as with neurodegenerative diseases, such as Alzheimer’s Disease (AD). However, recent evidence indicates that early, soluble oligomers rather than fibrils are the toxic species in Alzheimer’s and other amyloid diseases. Amyloid β-Protein is responsible for AD, and one of its important fragments, Aβ (25-35), is found in the brain and shown to be neurotoxic. Tachykinin neuropeptides, including Kassinin and Neuromedin K, 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 mechanism of how these peptides reduce the toxicity of 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 (IM-MS) and molecular dynamic simulations, to study the aggregation pathways of Aβ (25-35), Kassinin, Neuromedin K and mixtures of the latter two peptides with Aβ (25-35). Neuromedin K was observed to remove the higher order oligomers of Aβ (25-35), hexamers and octamers, which are related to its toxicity. However, Kassinin promotes the formation of these higher order oligomers. It is possible that Neuromedin K reduces the toxicity of Aβ (25-35) by shortening the lifetime of assembly intermediates of Ab (25-35). We also observe that even though they have significant structural homology with Aβ (25-35), Kassinin and Neuromedin K only form oligomers up to pentamers, while Aβ (25-35) forms hexamers and octamers. The hexamer and octamers structures have been identified as cylindrins and beta barrels respectively, and these structures have been strongly correlated to toxic species. Why the two tachykinin peptides behave so differently when mixed with Aβ (25-35) is also discussed.

Neuropeptides: Neuromedin K and kassinin affect toxic Aβ (25-35) oligomers by different mechanisms

ACS Spring Meeting 2021

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