Neuroserpin binds Abeta and is a neuroprotective component of amyloid plaques in Alzheimer disease.
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.
Kinghorn
Kerri J
KJ
Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/Medical Research Council Building, Hills Road, Cambridge CB2 2XY, United Kingdom.
Crowther
Damian C
DC
Sharp
Lynda K
LK
Nerelius
Charlotte
C
Davis
Richard L
RL
Chang
Howard T
HT
Green
Clare
C
Gubb
David C
DC
Johansson
Jan
J
Lomas
David A
DA
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
D016229:Amyloid beta-Peptides; D009479:Neuropeptides; D010455:Peptides; D015843:Serpins; D014357:Trypsin; D000097522:Neuroserpin