Related Experiment Video
Updated: Aug 13, 2025
Delivery of Therapeutic siRNA to the CNS Using Cationic and Anionic Liposomes
Published on: July 23, 2016
The Expression of Cellular Prion Protein, PrPC, Favors pTau Propagation and Blocks NMDAR Signaling in Primary
Rafael Rivas-Santisteban1,2,3, Iu Raïch1,4,5, David Aguinaga2
1Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas (CiberNed), National Institute of Health Carlos III, 28029 Madrid, Spain.
Background:
The N-methyl-D-aspartate receptor (NMDAR) is a target in current treatments for Alzheimer's disease (AD). The human prion protein (PrPC) has an important role in the pathophysiology of AD. We hypothesized that PrPC modulates NMDA signaling, thus being a process associated with Alzheimer's disease.
Methods:
NMDAR signaling was characterized in the absence or presence of PrPC in cAMP level determination, mitogen-activated protein kinase (MAPK) pathway and label-free assays in homologous and heterologous systems. Bioluminescence resonance energy transfer was used to detect the formation of NMDAR-PrPC complexes. AXIS™ Axon Isolation Devices were used to determine axonal transport of Tau and pTau proteins in cortical primary neurons in the absence or presence of PrPC. Finally, proximity ligation assays were used to quantify NMDA-PrPC complex formation in neuronal primary cultures isolated from APPSw/Ind transgenic mice, an Alzheimer's disease model expressing the Indiana and Swedish mutated version of the human amyloid precursor protein (APP).
Results:
We discovered a direct interaction between the PrPC and the NMDAR and we found a negative modulation of NMDAR-mediated signaling due to the NMDAR-PrPC interaction. In mice primary neurons, we identified NMDA-PrPC complexes where PrPC was capable of blocking NMDAR-mediated effects. In addition, we observed how the presence of PrPC results in increased neurotoxicity and neuronal death. Similarly, in microglial primary cultures, we observed that PrPC caused a blockade of the NMDA receptor link to the MAPK signaling cascade. Interestingly, a significant increase in NMDA-PrPC macromolecular complexes was observed in cortical neurons isolated from the APPSw,Ind transgenic model of AD.
Conclusions:
PrPC can interact with the NMDAR, and the interaction results in the alteration of the receptor functionality. NMDAR-PrPC complexes are overexpressed in neurons of APPSw/Ind mouse brain. In addition, PrPC exacerbates axonal transport of Tau and pTau proteins.
Insights
The human prion protein (PrPC) directly interacts with the N-methyl-D-aspartate receptor (NMDAR), negatively impacting its signaling. This interaction increases neurotoxicity and exacerbates tau pathology in Alzheimer's disease models.
Area of Science:
- Neuroscience
- Molecular Biology
- Alzheimer's Disease Research
Background:
- The N-methyl-D-aspartate receptor (NMDAR) is a key target for Alzheimer's disease (AD) treatments.
- The human prion protein (PrPC) plays a significant role in AD pathophysiology.
- This study investigates the hypothesis that PrPC modulates NMDAR signaling in the context of AD.
Purpose of the Study:
- To investigate the direct interaction between PrPC and NMDAR.
- To determine how PrPC affects NMDAR-mediated signaling pathways.
- To assess the role of PrPC-NMDAR complexes in an Alzheimer's disease mouse model.
Main Methods:
- Characterization of NMDAR signaling in the presence and absence of PrPC using cAMP assays, MAPK pathway analysis, and label-free assays.
- Detection of NMDAR-PrPC complexes using bioluminescence resonance energy transfer (BRET).
- Assessment of Tau and pTau axonal transport using AXIS™ Axon Isolation Devices and quantification of NMDAR-PrPC complexes in APPSw/Ind mice.
Main Results:
- A direct interaction between PrPC and NMDAR was discovered, leading to negative modulation of NMDAR signaling.
- PrPC was found to block NMDAR-mediated effects in primary neurons, increasing neurotoxicity and neuronal death.
- PrPC blocked the NMDAR-MAPK signaling cascade in microglial cells, and increased NMDAR-PrPC complexes were observed in an AD mouse model.
Conclusions:
- PrPC interacts with NMDAR, altering its function and contributing to AD pathogenesis.
- NMDAR-PrPC complexes are overexpressed in the brains of APPSw/Ind mice, an AD model.
- PrPC exacerbates the axonal transport of Tau and pTau proteins, a hallmark of AD.
More Related Videos
10:38Author Spotlight: Understanding the Impact of Pathological Proteins on Axonal Transport in Neurodegenerative Diseases
Published on: December 22, 2023
09:12Modulation of Tau Subcellular Localization as a Tool to Investigate the Expression of Disease-related Genes
Published on: December 20, 2019