title: Amyloid-like fibril formation by tachykinin neuropeptides and its relevance to amyloid β-protein aggregation and toxicity.
abstract: Protein aggregation and amyloid formation are associated with both pathological conditions in humans such as Alzheimer's disease and native functions such as peptide hormone storage in the pituitary secretory granules in mammals. Here, we studied amyloid fibrils formation by three neuropeptides namely physalaemin, kassinin and substance P of tachykinin family using biophysical techniques including circular dichroism, thioflavin T, congo red binding and microscopy. All these neuropeptides under study have significant sequence similarity with Aβ(25-35) that is known to form neurotoxic amyloids. We found that all these peptides formed amyloid-like fibrils in vitro in the presence of heparin, and these amyloids were found to be nontoxic in neuronal cells. However, the extent of amyloid formation, structural transition, and morphology were different depending on the primary sequences of peptide. When Aβ(25-35) and Aβ40 were incubated with each of these neuropeptides in 1:1 ratio, a drastic increase in amyloid growths were observed compared to that of individual peptides suggesting that co-aggregation of Aβ and these neuropeptides. The electron micrographs of these co-aggregates were dissimilar when compared with individual peptide fibrils further supporting the possible incorporation of these neuropeptides in Aβ amyloid fibrils. Further, the fibrils of these neuropeptides can seed the fibrils formation of Aβ40 and reduced the toxicity of preformed Aβ fibrils. The present study of amyloid formation by tachykinin neuropeptides is not only providing an understanding of the mechanism of amyloid fibril formation in general, but also offering plausible explanation that why these neuropeptide might reduce the cytotoxicity associated with Alzheimer's disease related amyloids.
authors.affiliation: Department of Biosciences and Bioengineering and Wadhwani Research Centre for Biosciences and Bioengineering, IIT Bombay, Powai, Mumbai 400076, India.
authors.forename: Pradeep K
authors.initials: PK
authors.lastname: Singh
authors.forename: Samir K
authors.initials: SK
authors.lastname: Maji
mesh_terms: D000465:Algorithms; D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry* / Q000494:pharmacology / Q000648:ultrastructure; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000648:ultrastructure; D052160:Benzothiazoles; D045744:Cell Line, Tumor; D002942:Circular Dichroism; D003224:Congo Red / Q000737:chemistry; D006493:Heparin / Q000737:chemistry; D006801:Humans; D015286:Kassinin / Q000737:chemistry* / Q000494:pharmacology; D008854:Microscopy, Electron; D009474:Neurons / Q000737:chemistry / Q000187:drug effects; D010446:Peptide Fragments / Q000737:chemistry* / Q000648:ultrastructure; D010803:Physalaemin / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding; D017433:Protein Structure, Secondary; D013373:Substance P / Q000737:chemistry / Q000494:pharmacology; D013844:Thiazoles / Q000737:chemistry; D018675:Toxicity Tests / Q000379:methods
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D010446:Peptide Fragments; D013844:Thiazoles; C074636:amyloid beta-protein (25-35); C009462:thioflavin T; D010803:Physalaemin; D013373:Substance P; D003224:Congo Red; D015286:Kassinin; D006493:Heparin