Amyloid-beta-stimulated plasminogen activation by tissue-type plasminogen activator results in processing of neuroendocrine factors.
Alzheimer's disease brain is characterized by the abundant presence of amyloid deposits. Accumulation of the major constituent of these deposits, amyloid-beta (Abeta), has been associated with decreased neurotransmission, increased neuronal cell death, and with cognitive decline. The mechanisms underlying these phenomena have not yet been fully elucidated. We have previously shown that amyloid peptides like Abeta bind tissue-type plasminogen activator (tPA) and cause enhanced plasmin production. Here we describe the identification of five major neuronal cell-produced Abeta-associated proteins and how Abeta-stimulated plasmin formation affects their processing. These five proteins are all neuroendocrine factors (NEFs): chromogranins A, B and C; truncated chromogranin B; and VGF. Plasminogen caused processing of Abeta-bound (but not soluble) tPA, chromogranin B and VGF and the degradation products were released from Abeta. Processing of the neuroendocrine factors was dependent on tPA as it was largely abrogated in tPA-/- cells or in the presence of a specific tPA-inhibitor. If plasmin indeed produces NEF-derived peptides in vivo, some of these peptides may have biological activity, for instance in regulating neurotransmitter release that may affect the pathology of Alzheimer's disease.
Kranenburg
O
O
Department of Medical Oncology, University Medical Center Utrecht, Utrecht, The Netherlands.
Gent
Y Y J
YY
Romijn
E P
EP
Voest
E E
EE
Heck
A J R
AJ
Gebbink
M F B G
MF
D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D019439:Chromaffin Cells / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D002864:Chromogranins / Q000378:metabolism; D005341:Fibrinolysin / Q000096:biosynthesis; D005455:Fluorescent Antibody Technique; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009414:Nerve Growth Factors; D009474:Neurons / Q000378:metabolism; D009479:Neuropeptides; D009490:Neurosecretory Systems / Q000187:drug effects*; D010449:Peptide Mapping; D010958:Plasminogen / Q000378:metabolism; D010960:Plasminogen Activators / Q000494:pharmacology*; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism; D010959:Tissue Plasminogen Activator / Q000494:pharmacology*
D016229:Amyloid beta-Peptides; D002864:Chromogranins; D009414:Nerve Growth Factors; D009479:Neuropeptides; D011506:Proteins; C512697:Vgf protein, mouse; D010958:Plasminogen; D010960:Plasminogen Activators; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin