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Published on: September 15, 2011
Megalin interacts with APP and the intracellular adapter protein FE65 in neurons
Ximena Alvira-Botero1, Rocío Pérez-Gonzalez, Carlos Spuch
1Laboratory of Neuroscience, Research Center, Hospital 12 de Octubre, 28041 Madrid, Spain.
Abstract:
Increasing evidence has implicated megalin, a low-density lipoprotein receptor-related protein, in the pathogenesis of Alzheimer's disease (AD). In the brain, megalin is expressed in brain capillaries, ependymal cells and choroid plexus, where it participates in the clearance of brain amyloid β-peptide (Aβ) complex. Recently, megalin has also been detected in oligodendrocytes and astrocytes. In this study we demonstrate that megalin is widely distributed in neurons throughout the brain. Additionally, given that FE65 mediates the interaction between the low density lipoprotein receptor-related protein-1 and the amyloid precursor protein (APP) to modulate the rate of APP internalization from the cell surface, we hypothesize that megalin could also interact with APP in neurons. Our results confirm that megalin interacts with APP and FE65, suggesting that these three proteins form a tripartite complex. Moreover, our findings imply that megalin may participate in neurite branching. Taken together, these results indicate that megalin has an important role in Aβ-mediated neurotoxicity, and therefore may be involved in the neurodegenerative processes that occur in AD.
Insights
Megalins role in Alzheimer's disease (AD) is explored, revealing its interaction with amyloid precursor protein (APP) and FE65 in neurons. This suggests megalin's involvement in neurotoxicity and neurodegenerative processes in AD.
Area of Science:
- Neuroscience
- Molecular Biology
- Cell Biology
Background:
- Alzheimer's disease (AD) pathogenesis involves complex molecular interactions.
- Megalin, a low-density lipoprotein receptor-related protein, is implicated in amyloid β-peptide (Aβ) clearance.
- Previous studies identified megalin in brain vasculature, ependymal cells, and choroid plexus.
Purpose of the Study:
- To investigate the distribution of megalin in neurons.
- To determine if megalin interacts with amyloid precursor protein (APP) and FE65 in neurons.
- To elucidate megalin's role in neuronal function and AD pathogenesis.
Main Methods:
- Immunohistochemistry to detect megalin distribution in the brain.
- Co-immunoprecipitation assays to assess protein-protein interactions.
- Cellular assays to evaluate megalin's effect on neurite branching.
Main Results:
- Megalin is widely distributed in neurons throughout the brain.
- Megalin directly interacts with APP and FE65, forming a tripartite complex.
- Megalin influences neurite branching and may contribute to Aβ-mediated neurotoxicity.
Conclusions:
- Megalin plays a significant role in neuronal cells, interacting with APP and FE65.
- The megalin-APP-FE65 complex may be crucial for regulating APP processing and neuronal function.
- Megalin is implicated in the neurodegenerative processes of Alzheimer's disease, highlighting its potential as a therapeutic target.
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