The Expression of Cellular Prion Protein, PrPC, Favors pTau Propagation and Blocks NMDAR Signaling in Primary Cortical Neurons
Rivas-Santisteban, Rafael (Universitat de Barcelona. Institut de Neurociències)
Raïch, Iu (Universitat de Barcelona. Departament de Bioquímica i Fisiologia)
Aguinaga Andrés, David (Universitat de Barcelona. Departament de Bioquímica i Biomedicina Molecular)
Saura Antolín, Carlos (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Franco, Rafael (Universitat de Barcelona. Facultat de Química)
Navarro Brugal, Gemma (Universitat de Barcelona. Departament de Bioquímica i Fisiologia)

Date:	2023
Abstract:	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 APP 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 APP 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 APP mouse brain. In addition, PrPC exacerbates axonal transport of Tau and pTau proteins.
Grants:	Agencia Estatal de Investigación PID2020-113430RB-I00 Agencia Estatal de Investigación PID2019-106615RB-100
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Alzheimer's disease ; NMDA ; Prion protein ; Tau protein ; Ptau protein ; Axonal transport
Published in:	Cells, Vol. 12 (january 2023) , ISSN 2073-4409

DOI: 10.3390/cells12020283
PMID: 36672218

18 p, 1.7 MB

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