Inhibition of long-term potentiation development in rat hippocampal slice by alpha 2-macroglobulin, an acute-phase protein in the brain.
alpha-Macroglobulins/*pharmacology; Animals; Electric Stimulation; Hippocampus/drug effects/*physiology; Humans; In Vitro Techniques; Long-Term Potentiation/*drug effects; Methylamines/pharmacology; Neurites/drug effects/*physiology; Pyramidal Cells/drug effects/physiology; Rats; Synapses/drug effects/physiology; Synaptic Transmission/drug effects; Time Factors
Alpha-2-macroglobulin (alpha 2M) in the rat and human brain is an acute-phase protein synthesized primarily by astrocytes, and it has been implicated in Alzheimer's disease and other neuropathological processes. The activated forms of alpha 2M, but not the native form, can suppress the neurite outgrowth of the central neurons, presumably through binding to neurotrophic factors and through direct inhibition of neurotrophic factor receptor signal transduction. Since neurotrophic factors are known to be involved in synaptic plasticity, we tested the effect of both the native and methylamine-activated (MA-alpha 2M) forms of alpha 2M on long-term potentiation (LTP) in area CA1 of adult rat hippocampal slice. Neither native alpha 2M nor MA-alpha 2M had an effect on baseline synaptic transmission. LTP induced by 200-Hz trains in the presence of 1.4 microM or 0.14 microM native alpha 2M was indistinguishable from control LTP. Although the presence of MA-alpha 2M at the same concentrations did not interfere with LTP induction, the development and maintenance of potentiation was blocked in a concentration-dependent time course. Results of this study indicate that the accumulation and activation of alpha 2M with inflammatory neuropathologies such as Alzheimer's disease can inhibit synaptic plasticity, which might partly account for the memory deficits seen in these patients.
Cavus I; Koo P H; Teyler T J
Journal of neuroscience research
1996
1996-02
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1002/(SICI)1097-4547(19960201)43:3%3C282::AID-JNR3%3E3.0.CO;2-F" target="_blank" rel="noreferrer noopener">10.1002/(SICI)1097-4547(19960201)43:3%3C282::AID-JNR3%3E3.0.CO;2-F</a>
Monoamine-activated alpha 2-macroglobulin binds trk receptor and inhibits nerve growth factor-stimulated trk phosphorylation and signal transduction.
Humans; Male; Animals; Mice; Signal Transduction/drug effects/*physiology; Phosphorylation; PC12 Cells; Protein-Serine-Threonine Kinases/metabolism; Neurites/drug effects/*physiology; Nerve Growth Factors/*pharmacology; Adrenal Gland Neoplasms; alpha-Macroglobulins/isolation & purification/*metabolism/pharmacology; ErbB Receptors/isolation & purification/metabolism; Fibrinolysin/metabolism; Mitogen-Activated Protein Kinase 1; Pheochromocytoma; Protein-Tyrosine Kinases/metabolism; Proto-Oncogene Proteins/drug effects/isolation & purification/*metabolism; Receptor Protein-Tyrosine Kinases/drug effects/isolation & purification/*metabolism; Serotonin/*metabolism/pharmacology; Receptors; Receptor; Nerve Growth Factor/drug effects/isolation & purification/*metabolism; Platelet-Derived Growth Factor/isolation & purification/metabolism; trkA
Monoamine-activated alpha 2-macroglobulin (alpha 2M) has been shown to inhibit beta-nerve growth factor (NGF)-promoted neurite outgrowth and the survival of embryonic sensory and forebrain neurons, whereas normal alpha 2M has little or no such activity. The objective of this study is to elucidate the mechanism of inhibition by monoamine-activated alpha 2M. Methylamine-activated alpha 2M (MA-alpha 2M) and serotonin-activated alpha 2M (5HT-alpha 2M) dose dependently inhibit NGF-promoted neurite outgrowth of the pheochromocytoma PC12 cell and its subline PC12(6-24) which overexpresses human trk protooncogene product, but have no effect on their viability, and this inhibition can be blocked by high concentrations of NGF. The binding of MA-alpha 2M to trk, which is a part of high-affinity NGF receptor, was studied with PC12(6-24) cells and NIH-3T3 fibroblasts expressing trk (trk-3T3). In each case MA-alpha 2M readily forms stable complexes with trk in vivo, whereas normal alpha 2M does not. Both
Koo P H; Qiu W S
The Journal of biological chemistry
1994
1994-02
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
Rat alpha1-macroglobulin enhances nerve growth factor-promoted neurite outgrowth, TrkA phosphorylation, and gene expression of pheochromocytoma PC12 cells.
Animals; Phosphorylation/drug effects; Rats; Transcription Factors/genetics; Gene Expression/*drug effects; Nerve Growth Factor/*pharmacology; *Immediate-Early Proteins; alpha-Macroglobulins/drug effects/metabolism/*pharmacology; Carrier Proteins; DNA-Binding Proteins/genetics; Early Growth Response Protein 1; Matrix Metalloproteinase 3/metabolism; Membrane Proteins; Nerve Growth Factors/genetics; Neurites/drug effects/*physiology; PC12 Cells/drug effects/metabolism/*physiology; Proto-Oncogene Proteins c-jun/genetics; Serotonin/pharmacology; Sprague-Dawley; Receptor; trkA/*metabolism
Monoamine-activated human alpha2-macroglobulin (alpha2M) has been previously demonstrated to inhibit TrkA-, TrkB-, and TrkC-mediated signal transduction. Rat alpha1-macroglobulin (alpha1M) and alpha2M are structural homologues of human alpha2M, but rat alpha1M is distinctly different from rat alpha2M in many ways and its role in the mammalian nervous system is unknown. In this report, monoamine-activated rat alpha1M was demonstrated to enhance in a dose-dependent manner nerve growth factor (NGF)-promoted neurite outgrowth in pheochromocytoma PC12 cells. Monoamine-activated alpha1M by itself, however, was neither neurotrophic nor mitogenic to PC12 cells. To investigate further its possible mode of action, the ability of monoamine-activated alpha1M and normal alpha1M to bind and to activate the NGF receptor (TrkA) was investigated. Monoamine-activated alpha1M formed a more stable complex with TrkA than normal alpha1 M, but the binding of monoamine-activated alpha1M to TrkA was adversely affected by prior stimulation of TrkA with NGF. In addition, monoamine-activated alpha1M enhanced the NGF-promoted TrkA phosphorylation and up-regulated the expression of NGF-inducible immediate-early genes (c-jun and NGFI-A) and delayed-response genes (SCG10 and transin) in PC12 cells; normal alpha1M, in contrast, produced little or no effect. This study demonstrates that alpha1M, the constitutive form of alpha-macroglobulin in the rat, possesses the ability to promote NGF-mediated differentiation in PC12 cells, possibly via its direct action on TrkA receptors and TrkA-mediated signal transduction and gene expression.
Lee P G; Koo P H
Journal of neurochemistry
2000
2000-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).