The association between prion proteins and Aβ₁₋₄₂ oligomers in cytotoxicity and apoptosis.

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.