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Alpha1-antichymotrypsin/Alzheimer's peptide Abeta(1-42) complex perturbs lipid metabolism and activates transcription factors PPARgamma and NFkappaB in human neuroblastoma (Kelly) cells.

Sun, Yongxin LU ; Wright, H T and Janciauskiene, Sabina LU (2002) In Journal of Neuroscience Research 67(4). p.511-522
Abstract
Amyloid-beta peptide (A) and the serpin proteinase inhibitor 1-antichymotrypsin (ACT) are components of the amyloid plaques associated with Alzheimer's disease (AD). A exists in soluble monomeric and oligomeric forms and in an insoluble polymerised fibrillar form, but it is not clear which of these plays the most important role in the etiology of AD. In vitro, A1-42 interacts with ACT, and as a result of this, ACT loses its proteinase inhibitor activity and polymerisation of A1-42 is promoted. Here we provide evidence that new molecular forms resulting from incubation of ACT with A1-42 have multiple cellular level effects on neuronal cells. The mixture of soluble A and an ACT/A complex formed by 2 hr incubation at a 10:1 molar ratio of... (More)
Amyloid-beta peptide (A) and the serpin proteinase inhibitor 1-antichymotrypsin (ACT) are components of the amyloid plaques associated with Alzheimer's disease (AD). A exists in soluble monomeric and oligomeric forms and in an insoluble polymerised fibrillar form, but it is not clear which of these plays the most important role in the etiology of AD. In vitro, A1-42 interacts with ACT, and as a result of this, ACT loses its proteinase inhibitor activity and polymerisation of A1-42 is promoted. Here we provide evidence that new molecular forms resulting from incubation of ACT with A1-42 have multiple cellular level effects on neuronal cells. The mixture of soluble A and an ACT/A complex formed by 2 hr incubation at a 10:1 molar ratio of A:ACT strongly induce cellular proliferation and expression of transcription factors peroxisome proliferator-activated receptor-gamma (PPAR) and NFB, and also increase uptake and depress degradation of native and oxidised low-density lipoprotein (LDL) by cells. Similar but less pronounced effects are seen when cells are exposed to the A peptide alone preincubated for 2 hr. A1-42 and to a lesser extent ACT/A1-42 complex mixture prepared by 2 hr incubation both inhibit association of native LDL with cells. Neither ACT alone nor the A1-42 and ACT/A1-42 forms prepared by 24-hr incubation show any significant effects in these assays. We propose that specific molecular forms of A1-42 and ACT/A1-42 complex mixture, both dependent on the abundances of A1-42 and ACT/A1-42 in vivo and on their time of exposure to each other, have cellular effects which are important for the initiation and progression of the pathologies associated with AD. (Less)
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keywords
Human, Lipids: metabolism, Lipoproteins, LDL: metabolism, NF-kappa B: drug effects, NF-kappa B: metabolism, Neuroblastoma, Neurons: enzymology, Neurons: pathology, Gene Expression Regulation: physiology, Brain: physiopathology, Cell Division: drug effects, Cell Division: physiology, Electrophoresis, Gene Expression Regulation: drug effects, Brain: enzymology, Binding Sites: drug effects, Binding Sites: physiology, Amyloid beta-Protein: metabolism, Amyloid beta-Protein: pharmacology, Alzheimer Disease: physiopathology, Alzheimer Disease: enzymology, LDL: drug effects, Oxidation-Reduction: drug effects, Peptide Fragments: metabolism, Peptide Fragments: pharmacology, Receptors, Cytoplasmic and Nuclear: drug effects, Cytoplasmic and Nuclear: metabolism, Senile Plaques: enzymology, Support, Non-U.S. Gov't, Transcription Factors: drug effects, Transcription Factors: metabolism, Transcription, Genetic: drug effects, Genetic: physiology, Tumor Cells, Cultured, alpha 1-Antichymotrypsin: metabolism, alpha 1-Antichymotrypsin: pharmacology
in
Journal of Neuroscience Research
volume
67
issue
4
pages
511 - 522
publisher
John Wiley & Sons
external identifiers
  • pmid:11835318
  • wos:000173607600011
  • scopus:0037082305
ISSN
1097-4547
DOI
10.1002/jnr.10144
language
English
LU publication?
yes
id
17429eb1-069e-4025-b621-7baa5a02a765 (old id 115581)
date added to LUP
2007-07-30 14:30:45
date last changed
2017-12-10 04:29:13
@article{17429eb1-069e-4025-b621-7baa5a02a765,
  abstract     = {Amyloid-beta peptide (A) and the serpin proteinase inhibitor 1-antichymotrypsin (ACT) are components of the amyloid plaques associated with Alzheimer's disease (AD). A exists in soluble monomeric and oligomeric forms and in an insoluble polymerised fibrillar form, but it is not clear which of these plays the most important role in the etiology of AD. In vitro, A1-42 interacts with ACT, and as a result of this, ACT loses its proteinase inhibitor activity and polymerisation of A1-42 is promoted. Here we provide evidence that new molecular forms resulting from incubation of ACT with A1-42 have multiple cellular level effects on neuronal cells. The mixture of soluble A and an ACT/A complex formed by 2 hr incubation at a 10:1 molar ratio of A:ACT strongly induce cellular proliferation and expression of transcription factors peroxisome proliferator-activated receptor-gamma (PPAR) and NFB, and also increase uptake and depress degradation of native and oxidised low-density lipoprotein (LDL) by cells. Similar but less pronounced effects are seen when cells are exposed to the A peptide alone preincubated for 2 hr. A1-42 and to a lesser extent ACT/A1-42 complex mixture prepared by 2 hr incubation both inhibit association of native LDL with cells. Neither ACT alone nor the A1-42 and ACT/A1-42 forms prepared by 24-hr incubation show any significant effects in these assays. We propose that specific molecular forms of A1-42 and ACT/A1-42 complex mixture, both dependent on the abundances of A1-42 and ACT/A1-42 in vivo and on their time of exposure to each other, have cellular effects which are important for the initiation and progression of the pathologies associated with AD.},
  author       = {Sun, Yongxin and Wright, H T and Janciauskiene, Sabina},
  issn         = {1097-4547},
  keyword      = {Human,Lipids: metabolism,Lipoproteins,LDL: metabolism,NF-kappa B: drug effects,NF-kappa B: metabolism,Neuroblastoma,Neurons: enzymology,Neurons: pathology,Gene Expression Regulation: physiology,Brain: physiopathology,Cell Division: drug effects,Cell Division: physiology,Electrophoresis,Gene Expression Regulation: drug effects,Brain: enzymology,Binding Sites: drug effects,Binding Sites: physiology,Amyloid beta-Protein: metabolism,Amyloid beta-Protein: pharmacology,Alzheimer Disease: physiopathology,Alzheimer Disease: enzymology,LDL: drug effects,Oxidation-Reduction: drug effects,Peptide Fragments: metabolism,Peptide Fragments: pharmacology,Receptors,Cytoplasmic and Nuclear: drug effects,Cytoplasmic and Nuclear: metabolism,Senile Plaques: enzymology,Support,Non-U.S. Gov't,Transcription Factors: drug effects,Transcription Factors: metabolism,Transcription,Genetic: drug effects,Genetic: physiology,Tumor Cells,Cultured,alpha 1-Antichymotrypsin: metabolism,alpha 1-Antichymotrypsin: pharmacology},
  language     = {eng},
  number       = {4},
  pages        = {511--522},
  publisher    = {John Wiley & Sons},
  series       = {Journal of Neuroscience Research},
  title        = {Alpha1-antichymotrypsin/Alzheimer's peptide Abeta(1-42) complex perturbs lipid metabolism and activates transcription factors PPARgamma and NFkappaB in human neuroblastoma (Kelly) cells.},
  url          = {http://dx.doi.org/10.1002/jnr.10144},
  volume       = {67},
  year         = {2002},
}