Beta-amyloid (Abeta) causes detachment of N1E-115 neuroblastoma cells by acting as a scaffold for cell-associated plasminogen activation.
A major component of neuritic plaques in brain tissue of Alzheimer's disease patients is the beta-amyloid peptide (Abeta). Accumulation of Abeta has been associated with increased neuronal cell death and cognitive decline. We have previously shown that amyloid peptides like Abeta bind tissue-type plasminogen activator (tPA) and stimulate plasmin production. Here we investigated how Abeta regulates plasmin formation by N1E-115 neuroblastoma cells and the effects of Abeta-mediated plasmin formation on cell attachment and cell survival. We find that Abeta induces excessive cell-associated plasmin generation that causes cell detachment. Cell detachment is inhibited by carboxypeptidase B (CPB), an enzyme that blocks plasmin formation by cleaving off C-terminal lysine residues. Plasmin and CPB control Abeta-induced cell detachment independently of direct effects on cell viability. Abeta40 as well as oligomeric and fibrillar forms of Abeta42 stimulated tPA-mediated plasminogen activation and cell detachment. Our results suggest that plasmin-mediated cell detachment could contribute to the pathological effects of Abeta in diseased brain.
Kranenburg
Onno
O
Department of Medical Oncology, University Medical Center Utrecht, Utrecht, The Netherlands.
Bouma
Barend
B
Gent
Yoony Y J
YY
Aarsman
Colinda J
CJ
Kayed
Rakez
R
Posthuma
George
G
Schiks
Bettina
B
Voest
Emile E
EE
Gebbink
Martijn F B G
MF
D000544:Alzheimer Disease / Q000378:metabolism* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D043424:Carboxypeptidase B / Q000378:metabolism / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D005341:Fibrinolysin / Q000096:biosynthesis*; D051379:Mice; D009447:Neuroblastoma; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology; D058225:Plaque, Amyloid / Q000378:metabolism*; D010958:Plasminogen / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D010959:Tissue Plasminogen Activator / Q000378:metabolism; D014407:Tumor Cells, Cultured
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D010958:Plasminogen; D043424:Carboxypeptidase B; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin