The Expression of Cellular Prion Protein, PrPC, Favors pTau Propagation and Blocks NMDAR Signaling in Primary Cortical Neurons

Cells. 2023 Jan 11;12(2):283. doi: 10.3390/cells12020283.

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 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.

Keywords: Alzheimer’s disease; NMDA; Tau protein; axonal transport; pTau protein; prion protein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease* / metabolism
  • Amyloid beta-Protein Precursor / metabolism
  • Animals
  • Humans
  • Mice
  • Mice, Transgenic
  • N-Methylaspartate / metabolism
  • N-Methylaspartate / pharmacology
  • Neurons / metabolism
  • Phosphorylation
  • Prion Proteins / metabolism
  • Receptors, N-Methyl-D-Aspartate / metabolism

Substances

  • Receptors, N-Methyl-D-Aspartate
  • Prion Proteins
  • N-Methylaspartate
  • Amyloid beta-Protein Precursor

Grants and funding

This work was partially supported by the AARFD-17-503612 grant (to GN) from the US Alzheimer’s Association, and by grants PID2020-113430RB-I00 (to GN) and PID2019-106615RB-100 (to CAS) from the Spanish Ministerio de Ciencia, Innovación y Universidades (MCIU; or equivalent) and the Spanish Agencia Estatal de Investigación (AEI); they include UE FEDER funds. The research group of the University of Barcelona is considered distinguished (group consolidate #2017 SGR 1497) by the Regional Catalonian Government, which does not provide any specific funding for reagents or for payment of services or open access fees).