PMID- 36672218 OWN - NLM STAT- MEDLINE DCOM- 20230124 LR - 20230212 IS - 2073-4409 (Electronic) IS - 2073-4409 (Linking) VI - 12 IP - 2 DP - 2023 Jan 11 TI - The Expression of Cellular Prion Protein, PrPC, Favors pTau Propagation and Blocks NMDAR Signaling in Primary Cortical Neurons. LID - 10.3390/cells12020283 [doi] LID - 283 AB - 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(Sw/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 APP(Sw,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 APP(Sw/Ind) mouse brain. In addition, PrPC exacerbates axonal transport of Tau and pTau proteins. FAU - Rivas-Santisteban, Rafael AU - Rivas-Santisteban R AD - Centro de Investigacion Biomedica en Red Enfermedades Neurodegenerativas (CiberNed), National Institute of Health Carlos III, 28029 Madrid, Spain. AD - Departament de Bioquimica i Biomedicina Molecular, Universitat de Barcelona, 08028 Barcelona, Spain. AD - Institute of Neuroscience (NeuroUB), University of Barcelona, Av. Joan XXIII 27-31, 08028 Barcelona, Spain. FAU - Raich, Iu AU - Raich I AUID- ORCID: 0000-0001-6271-0495 AD - Centro de Investigacion Biomedica en Red Enfermedades Neurodegenerativas (CiberNed), National Institute of Health Carlos III, 28029 Madrid, Spain. AD - Department de Bioquimica i Biologia Molecular, Universitat Autonoma de Barcelona, 08193 Barcelona, Spain. AD - Department of Biochemistry and Physiology, Faculty of Pharmacy and Food Science, University of Barcelona, 08028 Barcelona, Spain. FAU - Aguinaga, David AU - Aguinaga D AD - Departament de Bioquimica i Biomedicina Molecular, Universitat de Barcelona, 08028 Barcelona, Spain. FAU - Saura, Carlos A AU - Saura CA AUID- ORCID: 0000-0003-3692-5657 AD - Institute of Neuroscience (NeuroUB), University of Barcelona, Av. Joan XXIII 27-31, 08028 Barcelona, Spain. AD - Department de Bioquimica i Biologia Molecular, Universitat Autonoma de Barcelona, 08193 Barcelona, Spain. FAU - Franco, Rafael AU - Franco R AUID- ORCID: 0000-0003-2549-4919 AD - Centro de Investigacion Biomedica en Red Enfermedades Neurodegenerativas (CiberNed), National Institute of Health Carlos III, 28029 Madrid, Spain. AD - Departament de Bioquimica i Biomedicina Molecular, Universitat de Barcelona, 08028 Barcelona, Spain. AD - School of Chemistry, University of Barcelona, 08028 Barcelona, Spain. FAU - Navarro, Gemma AU - Navarro G AUID- ORCID: 0000-0003-4654-0873 AD - Centro de Investigacion Biomedica en Red Enfermedades Neurodegenerativas (CiberNed), National Institute of Health Carlos III, 28029 Madrid, Spain. AD - Department de Bioquimica i Biologia Molecular, Universitat Autonoma de Barcelona, 08193 Barcelona, Spain. AD - Department of Biochemistry and Physiology, Faculty of Pharmacy and Food Science, University of Barcelona, 08028 Barcelona, Spain. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230111 PL - Switzerland TA - Cells JT - Cells JID - 101600052 RN - 0 (Receptors, N-Methyl-D-Aspartate) RN - 0 (Prion Proteins) RN - 6384-92-5 (N-Methylaspartate) RN - 0 (Amyloid beta-Protein Precursor) SB - IM MH - Mice MH - Humans MH - Animals MH - *Alzheimer Disease/metabolism MH - Receptors, N-Methyl-D-Aspartate/metabolism MH - Prion Proteins/metabolism MH - N-Methylaspartate/pharmacology/metabolism MH - Phosphorylation MH - Neurons/metabolism MH - Amyloid beta-Protein Precursor/metabolism MH - Mice, Transgenic PMC - PMC9856489 OTO - NOTNLM OT - Alzheimer's disease OT - NMDA OT - Tau protein OT - axonal transport OT - pTau protein OT - prion protein COIS- The authors declare no conflict of interest. EDAT- 2023/01/22 06:00 MHDA- 2023/01/25 06:00 PMCR- 2023/01/11 CRDT- 2023/01/21 01:11 PHST- 2022/11/18 00:00 [received] PHST- 2022/12/14 00:00 [revised] PHST- 2022/12/30 00:00 [accepted] PHST- 2023/01/21 01:11 [entrez] PHST- 2023/01/22 06:00 [pubmed] PHST- 2023/01/25 06:00 [medline] PHST- 2023/01/11 00:00 [pmc-release] AID - cells12020283 [pii] AID - cells-12-00283 [pii] AID - 10.3390/cells12020283 [doi] PST - epublish SO - Cells. 2023 Jan 11;12(2):283. doi: 10.3390/cells12020283.