title: Neuroserpin binds Abeta and is a neuroprotective component of amyloid plaques in Alzheimer disease.
abstract: Alzheimer disease is characterized by extracellular plaques composed of Abeta peptides. We show here that these plaques also contain the serine protease inhibitor neuroserpin and that neuroserpin forms a 1:1 binary complex with the N-terminal or middle parts of the Abeta(1-42) peptide. This complex inactivates neuroserpin as an inhibitor of tissue plasminogen activator and blocks the loop-sheet polymerization process that is characteristic of members of the serpin superfamily. In contrast neuroserpin accelerates the aggregation of Abeta(1-42) with the resulting species having an appearance that is distinct from the mature amyloid fibril. Neuroserpin reduces the cytotoxicity of Abeta(1-42) when assessed using standard cell assays, and the interaction has been confirmed in vivo in novel Drosophila models of disease. Taken together, these data show that neuroserpin interacts with Abeta(1-42) to form off-pathway non-toxic oligomers and so protects neurons in Alzheimer disease.
authors.affiliation: Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/Medical Research Council Building, Hills Road, Cambridge CB2 2XY, United Kingdom.
authors.forename: Kerri J
authors.initials: KJ
authors.lastname: Kinghorn
authors.forename: Damian C
authors.initials: DC
authors.lastname: Crowther
authors.forename: Lynda K
authors.initials: LK
authors.lastname: Sharp
authors.forename: Charlotte
authors.initials: C
authors.lastname: Nerelius
authors.forename: Richard L
authors.initials: RL
authors.lastname: Davis
authors.forename: Howard T
authors.initials: HT
authors.lastname: Chang
authors.forename: Clare
authors.initials: C
authors.lastname: Green
authors.forename: David C
authors.initials: DC
authors.lastname: Gubb
authors.forename: Jan
authors.initials: J
authors.lastname: Johansson
authors.forename: David A
authors.initials: DA
authors.lastname: Lomas
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D000818:Animals; D055592:Biophysical Phenomena; D001703:Biophysics; D004330:Drosophila; D006801:Humans; D009479:Neuropeptides / Q000737:chemistry*; D016716:PC12 Cells; D010455:Peptides / Q000737:chemistry; D058225:Plaque, Amyloid / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051381:Rats; D015843:Serpins / Q000737:chemistry*; D014357:Trypsin / Q000737:chemistry; D000097522:Neuroserpin
chemical_list: D016229:Amyloid beta-Peptides; D009479:Neuropeptides; D010455:Peptides; D015843:Serpins; D014357:Trypsin; D000097522:Neuroserpin