The association between prion proteins and Aβ 1-42 oligomers in cytotoxicity and apoptosis

摘要

Misfolding of prion protein (PrP to PrPSc) can cause neurodegenerative prion diseases. As a glycosylphosphatidylinositol (GPI)-anchored membrane protein, the normal form of PrP (PrPC) can function as a receptor for ligands in the extracellular space. PrPC was suggested to be involved in memory, synaptic neuronal communication, and anti-oxidation as a neuroprotective agent. The recently identified interaction between PrPC and Aβ 1-42 oligomers suggested another role for PrP as a receptor for Aβ 1-42 oligomers, thereby influencing cytotoxicity and apoptosis.Here, the association between PrPC and Aβ 1-42 oligomers was investigated by visualizing protein localization in neuronal cells by immunocytochemistry. Aβ 1-42 oligomer-induced cytotoxicity was tested in respective expressions of PrPC by using mouse neuroblastoma-2a (N2a) cells, the prion protein overexpressed cells (L2-2B1), and a Prnp-null mouse hippocampal cell line (HpL 3-4). Moreover, apoptotic proteins such as caspase-8 were used to assess the effect of PrPC on Aβ 1-42 oligomer-mediated apoptosis. In L2-2B1 and HpL 3-4 cells, the difference in the cytotoxicity of Aβ 1-42 oligomers could be clearly distinguished. In addition, Aβ 1-42 oligomers induced mitochondria dysfunction, reactive oxygen species (ROS) generation, and calcium influx PrPC-dependently. Apoptosis, related to mitochondria dysfunction, was further investigated to determine the cytotoxic pathway; the results suggest that PrPC could be involved in both the intrinsic and extrinsic apoptotic pathways. Finally, cells with abundant PrPC expression seemed to be more susceptible to Aβ 1-42 oligomer toxicity, suggesting the importance of the level of PrPC expression in the induction of apoptosis.