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Expression of alpha(2)-macroglobulin receptor/low density lipoprotein receptor-related protein (LRP) in rat
M P Marzolo1, R von Bernhardi, G Bu
1Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.
Abstract:
Low density lipoprotein receptor-related protein (LRP) participates in the uptake and degradation of several ligands implicated in neuronal pathophysiology including apolipoprotein E (apoE), activated alpha(2) -macroglobulin (alpha(2)M*) and beta-amyloid precursor protein (APP). The receptor is expressed in a variety of tissues. In the brain LRP is present in pyramidal-type neurons in cortical and hippocampal regions and in astrocytes that are activated as a result of injury or neoplasmic transformation. As LRP is expressed in the monocyte/macrophage cell system, we were interested in examining whether LRP is expressed in microglia. We isolated glial cells from the brain of neonatal rats and LRP was immunodetected both in microglial cells and in astrocytes expressing glial fibrillar acidic protein (GFAP). Microglial cells were able to bind and internalize LRP-specific ligand, alpha(2)M*. The internalization was inhibitable by RAP, with a Kd of 1.7 nM. The expression of LRP was up-regulated by dexamethasone, and down-regulated by lipopolysaccharide (LPS), gamma interferon (IFN-gamma) or a combination of both. LRP was less sensitive to dexamethasone in activated astrocytes than in microglia. We provided the first analysis of LRP expression and regulation in microglia. Our results open the possibility that microglial cells could be related to the participation of LRP and its ligands in different pathophysiological states in brain.
Insights
Low density lipoprotein receptor-related protein (LRP) is expressed in microglia, which can internalize LRP ligands. Microglial LRP expression is modulated by inflammatory signals, suggesting a role in brain pathophysiology.
Area of Science:
- Neuroscience
- Cell Biology
- Immunology
Background:
- Low density lipoprotein receptor-related protein (LRP) is crucial for neuronal pathophysiology, mediating the uptake of ligands like apolipoprotein E (apoE), activated alpha(2)-macroglobulin (alpha(2)M*), and beta-amyloid precursor protein (APP).
- LRP is found in brain neurons and activated astrocytes, and also in the monocyte/macrophage system.
Purpose of the Study:
- To investigate the expression and function of LRP in microglia, a key immune cell type in the brain.
- To determine how LRP expression in microglia is regulated by inflammatory stimuli.
Main Methods:
- Isolation of glial cells from neonatal rat brains.
- Immunodetection of LRP in microglial cells and astrocytes (GFAP-positive).
- Assessment of microglial binding and internalization of alpha(2)M*.
- Analysis of LRP regulation by dexamethasone, lipopolysaccharide (LPS), and gamma interferon (IFN-gamma).
Main Results:
- LRP was detected in both microglia and astrocytes.
- Microglia demonstrated the ability to bind and internalize the LRP ligand alpha(2)M*, with inhibition by RAP (Kd = 1.7 nM).
- LRP expression was upregulated by dexamethasone and downregulated by LPS and/or IFN-gamma, with differential sensitivity between microglia and activated astrocytes.
Conclusions:
- This study provides the first analysis of LRP expression and regulation in microglia.
- Microglia express functional LRP and their LRP levels are modulated by inflammatory conditions.
- These findings suggest a potential role for microglial LRP in brain pathophysiological states involving LRP ligands.